ATTACK CANCER TODAY BY APPROVED DRUG REPURPOSING
There are many sites that report cancer studies. Unfortunately cancer drugs take years before they can move from lab to prescriptions - as many as 10 years and only 10% or less can get FDA approval. Cancer mutates at manic pace and cancer patients do not have time. Through this blog I try to bring therapeutics that the patient can get administered today. Earlier post comprehensively covers natural molecules and compounds which have shown success in studies conducted by reputable labs against cancer. This blog was also amongst the very early ones to predict the importance of cancer immunotherapies.
In this post I am listing various approved therapeutics that a cancer patient can ask their doctor today to prescribe to them to combat their cancer. Recent major discoveries have shown drugs approved by FDA for a particular disease proving highly beneficial in another disease. Two greatest examples of such drug repurposing are Sidenafil originally approved for heart conditions and now prescribed for erectile dysfunction. The second example is Metformin prescribed for type 2 diabetes and recently found to have healthspan and lifespan extension abilities. Drug repurposing can be a very powerful weapon in the hands of cancer patients as it opens up hundreds of new relatively safe options that they can use right away to fight cancer.
Below are listed some such candidates:
1. Drug Cocktail: Wan L. et al. showed that a combination of 3 FDA-approved drugs, the over-the-counter drug aspirin, the well-known antibiotic doxycycline and mifepristone (a progesterone receptor antagonist known as an abortifacient pill) used together with the amino acid lysine could effectively and safely prevent cancer metastasis. Now metastasis or spread of cancer from its original site causes 90% of the cancer related deaths so this discovery is very valuable for cancer patients who are in early stages or can also mitigate recurrence. They stopped adhesion of cancer cell lines to either endothelial cells or extracellular matrix via down-regulating cell adhesion molecules ICAM-1 and α4-integrin. Without cancer cells being able to stick to blood vessel cells they can not rupture them and spread. In their in vivo experiment, a four-day pre-treatment followed by a 30-day oral administration of the quadruplet drug combination to mice inoculated with melanoma cells produced significant inhibition of cancer metastasis in the lung dose-dependently without any marked side effects. But all 4 need to be taken together for their synergistic benefit.
2. Nitazoxanide: an FDA-approved antiprotozoal drug with excellent pharmacokinetic and safety profile, is the only molecule among the screening hits that reaches high plasma concentrations persisting for up to a few hours after single oral dose. Nitazoxanide activated the AMPK pathway and downregulated c-Myc, mTOR, and Wnt signaling at clinically achievable concentrations. Nitazoxanide is given in combination with either irinotecan and Ketoconazole. Senkowski et al had in vivo success by combining it with irinotecan. Nazir M. developed a screening that identified the antifungal agent ketoconazole as selectively toxic to hypoxic and nutrient deprived cancer cells when combined with nitazoxanide.
3. Itraconazole: is a broad-spectrum anti-fungal agent. An emerging body of in vivo, in vitro and clinical evidence have confirmed that it also possesses antineoplastic activities and has a synergistic action when combined with other chemotherapeutic agents. It acts via several mechanisms to prevent tumour growth, including inhibition of the Hedgehog pathway, prevention of angiogenesis, decreased endothelial cell proliferation, cell cycle arrest and induction of auto-phagocytosis. These allow itraconazole, either alone or in combination with other cytotoxic agents, to increase drug efficacy and overcome drug resistance.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5588108/#!po=27.9762
This above is a link to review article by Rachel Pounds et al. It gives response data of patients with the following cancers: ovarian, prostrate, breast, lung, bcc, pancreatic, biliary tract, mycosis fungoides and acute leukaemia.
4. Mebendazole: What do an anti-parasitic drug used to treat pinworms and a frequently used anti-malarial drug have in common? According to recent studies from the labs of Johns Hopkins and University of Kentucky investigators, both mebendazole and chloroquine could be promising medicines to combat cancer. The Brain Cancer Biology and Therapy Research Laboratory discovered that pinworm-infected mice, which were treated with mebendazole, did not develop appreciable brain tumors, even though the researchers had implanted brain cancer cells weeks before. In subsequent experiments, his team demonstrated that administration of mebendazole prevented tumor proliferation and improved survival times in mice by an average of 63 percent. Mebendazole was part of a phase I clinical trial for patients with newly diagnosed, high-grade glioma and glioblastoma.
This Phase 1 trial was primarily devoted to determining the safety and preliminary efficacy of mebendazole in treating glioblastoma. It has recently been completed – with encouraging results. Based on the promise of these early results, ABC2 is now working with Dr. Riggins to move mebendazole into Phase 2 clinical trials designed to more rigorously test its efficacy as a potential new glioblastoma therapy. If this project is successful, mebendazole could provide a safe, inexpensive, effective glioblastoma treatment with the potential for rapid translation into the clinic. Because mebendozole has been used around the world for years to treat pinworm infections in children, it offers a particularly enticing opportunity as a treatment for pediatric brain tumors.Recently, Bai and colleagues demonstrated compelling preclinical evidence for using the microtubule inhibitory drug mebendazole (MBZ) to treat several molecular subtypes of medulloblastoma, including group 3. As a long-standing antihelminthic drug, MBZ has the advantage of a low-toxicity profile in children compared with other microtubule inhibitors such as vincristine and paclitaxel. As a lipophilic agent with a low molecular weight, MBZ has the additional advantage of blood-brain barrier permeability. Previous studies suggest that MBZ acts as an inhibitor of vascular endothelial growth factor (VEGF) receptor 2 (VEGFR2), the primary receptor mediating the effects of VEGF. This study reveals the antiangiogenic effect of MBZ in medulloblastoma preclinical mouse models and its encouraging impact on overall survival. In another study Dr. Symons and colleagues examined mebendazole, a medication that is used to treat parasitic pinworms and that in previous studies had been found to be effective in the treatment of glioma tumors. By studying how mebendazole kills isolated tumor cells in the laboratory, they showed that it works in exactly the same way as vincristine. They also found however, that while mebendazole effectively slowed down the growth of glioma tumors, vincristine did not work at all."We were rather surprised to see that vincristine, which is currently used to treat a range of different brain tumors, was totally ineffective in our in vivo glioma model," said Dr. Symons. "In contrast, in the same model, mebendazole performed quite well, most likely because mebendazole crosses the blood-brain barrier and reaches the tumor much better than vincristine. The reason that vincristine may be erroneously believed to be effective for the treatment of brain tumors is that it always has been used in combination with other treatments."Based on the new results -- and due to the fact that vincristine often has severe side effects in comparison to relatively mild reactions to mebendzole -- Dr. Symons and his team are now strongly motivated to initiate clinical trials to test whether vincristine can be exchanged by mebendazole in the treatment of brain tumors."Sometimes innovation can be looking at an existing treatment in a new light," said Kevin J. Tracey, MD, president and CEO of the Feinstein Institute. "This new approach needs to be tested in clinical trials, but with Dr. Symons' new findings we may be closer to a new treatment option that could prolong the lives of the patients suffering from low-grade glioma and other brain tumors." Another study by deWitt et al also came to the same conclusion finding Vincristine ineffective and mebendazole quite effective in various brain tumors.
5. Zardaverine + Quazinone: Nadir M.
showed that subgroups of tumors, within many different cancer types, overexpress PDE3A (mRNA and protein) and that PDE3A expression can predict sensitivity to phosphodiesterase inhibitors.
Searching the Human Protein Atlas database revealed that differential PDE3A expression, as observed in ovarian cancer specimens, is also prevalent in many other cancer types, including colorectal, melanoma, endometrial, testis and urothelial cancers. Their observations suggest that PDE3A has the potential to be both a biomarker of PDE sensitivity and drug target for cancer treatment.
6. Nelfinavir: earlier generation HIV drug with 15 years of safe use data has now been found to have multiple actions against cancer. It's action as monodrug is not as effective as an adjunct. Quoting a review article by Tomas K. "If apoptosis is described as a cascade, then apoptosis stimulator drugs like NFV should be viewed as enhancers of this cascade. An initiator of the cascade is still necessary, for example chemoradiotherapy. After this initial step, apoptosis stimulator drugs increase the amount of cells entering this pathway. This might be one of possible reasons why nelfinavir alone has shown poor results in a clinical trial used as monotherapy.
https://www.spandidos-publications.com/10.3892/or.2012.1840
8. CH05-10: An analog of Indinavir another PI has also shown broad spectrum anti cancer activity:
https://www.ncbi.nlm.nih.gov/m/pubmed/20946116/
9. Thalidomide + Lenalidomide: Thalidomide was originally developed to treat morning sickness in pregnant women. Its use was stopped because it was found to cause birth defects. Thalidomide is now used as a treatment for cancer, but it must not be taken in pregnancy. A pregnancy prevention programme must be followed during treatment. Thalidomide works in several different ways. It helps the immune system attack and destroy cancer cells. Kill or stop the growth of cancer cells. It affects the chemical messages that cancer cells need to survive. It blocks the development of new blood vessels which cancer cells need to grow and spread. Thalidomide is usually taken with other chemotherapy drugs and steroids as treatment for myeloma. The researchers at Dana Farber Cancer Institute demonstrated that lenalidomide — a more powerful derivative of thalidomide — killed multiple myeloma cells by disabling overactive switches called transcription factors that drive the cells' excessive growth. Transcription factors are proteins that bind to genes and increase their activity, and cancers are often driven by overactivity of these molecular switches. For example, a transcription factor called c-Myc appears to be overactive in many different types of cancer.
10. DMOG dimethyloxalylglycine:
A team of researchers from the U.K. and the U.S. has found that a drug used to study hypoxia can also be used to inhibit glutamine metabolism—a possible means for targeting cancer cells by cutting off their supply line. In their paper published in the journal Nature Chemical Biology. The researchers began their study by noting that a lot of tumors require glutamine to survive—they utilize it in a process called glutaminolysis. A drug called dimethyloxalylglycine (DMOG) might be useful in inhibiting glutamine used by cancer cells. Many types of cancer cells exhibit glutamine addiction. The growing cancer must synthesize nitrogenous compounds in the form of nucleotides and NEAAs. Glutamine is the obligate nitrogen donor. Glutamine’s contribution to amino acid biosynthesis establishes it as a key ingredient for the protein translation needs of cancer cells. A further role for glutamine in cancer cell protein translation stems from observations that a master regulator of protein translation, the mammalian target of rapamycin complex 1 (mTORC1), is responsive to glutamine levels. Glutamine consumption rate of many of the cancer cell lines exceeded the consumption of any other amino acid by ten-fold. Many cancer cell lines could not proliferate in the absence of exogenous glutamine and many could not maintain their viability in the absence of glutamine. Replenishment of the mitochondrial carbon pool by glutamine provides the mitochondria with precursors for the maintenance of mitochondrial membrane potential and for the synthesis of nucleotides, proteins, and lipids.
wide variety of human cancer cell lines have shown sensitivity to glutamine starvation, including those derived from pancreatic cancer, glioblastoma multiforme, acute myelogenous leukemia, colon cancer and small cell lung cancer.
11. Blocking Cancer Exosomes:
Tulane University scientists Abdel Mageed, Amrita Dutta, et al used robotic high throughput screening technique to identify approved compounds that could block cancer exosomes. Apparently cancer exosomes are implicated in the spread of cancer. So any drug that blocks cancer exosomes from bring released by cancer cells can be very valuable to cancer patients at all stages. It can also be taken as an adjunct. They screened 4,580 compounds. The lead compounds tipifarnib, neticonazole, climbazole, ketoconazole, and triademenol were validated as potent inhibitors.
12. Slowing down Cancer Metastasis:
I am a fan of young Johns Hopkins scientists Hasini Jayatilika. She and her colleagues discovered that it is not tumour size that triggers metastsis (parts breaking out to form tumours at other site) but it is tumour density that triggers metastasis. I reported about her significant discovery in one of my earlier posts on this blog.
After 7 years of research she demonstrated how after reaching a certain density tumour cells begin to release two proteins Interleukin 6 and Interleukin 8. They tell the new cancer cells that it is getting too crowded separate out and build your own nest at some other site. She observed this after studying the communications between cancer cells. She also discovered two approved drugs known to work on Interleukin receptors that significantly slowed down metastasis:
Tocilizumab a rheumatoid arthritis treatment and Reparixin a potential cancer drug. When combined they seemed to significantly slow down the metastasis.
3. Itraconazole: is a broad-spectrum anti-fungal agent. An emerging body of in vivo, in vitro and clinical evidence have confirmed that it also possesses antineoplastic activities and has a synergistic action when combined with other chemotherapeutic agents. It acts via several mechanisms to prevent tumour growth, including inhibition of the Hedgehog pathway, prevention of angiogenesis, decreased endothelial cell proliferation, cell cycle arrest and induction of auto-phagocytosis. These allow itraconazole, either alone or in combination with other cytotoxic agents, to increase drug efficacy and overcome drug resistance.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5588108/#!po=27.9762
This above is a link to review article by Rachel Pounds et al. It gives response data of patients with the following cancers: ovarian, prostrate, breast, lung, bcc, pancreatic, biliary tract, mycosis fungoides and acute leukaemia.
4. Mebendazole: What do an anti-parasitic drug used to treat pinworms and a frequently used anti-malarial drug have in common? According to recent studies from the labs of Johns Hopkins and University of Kentucky investigators, both mebendazole and chloroquine could be promising medicines to combat cancer. The Brain Cancer Biology and Therapy Research Laboratory discovered that pinworm-infected mice, which were treated with mebendazole, did not develop appreciable brain tumors, even though the researchers had implanted brain cancer cells weeks before. In subsequent experiments, his team demonstrated that administration of mebendazole prevented tumor proliferation and improved survival times in mice by an average of 63 percent. Mebendazole was part of a phase I clinical trial for patients with newly diagnosed, high-grade glioma and glioblastoma.
This Phase 1 trial was primarily devoted to determining the safety and preliminary efficacy of mebendazole in treating glioblastoma. It has recently been completed – with encouraging results. Based on the promise of these early results, ABC2 is now working with Dr. Riggins to move mebendazole into Phase 2 clinical trials designed to more rigorously test its efficacy as a potential new glioblastoma therapy. If this project is successful, mebendazole could provide a safe, inexpensive, effective glioblastoma treatment with the potential for rapid translation into the clinic. Because mebendozole has been used around the world for years to treat pinworm infections in children, it offers a particularly enticing opportunity as a treatment for pediatric brain tumors.Recently, Bai and colleagues demonstrated compelling preclinical evidence for using the microtubule inhibitory drug mebendazole (MBZ) to treat several molecular subtypes of medulloblastoma, including group 3. As a long-standing antihelminthic drug, MBZ has the advantage of a low-toxicity profile in children compared with other microtubule inhibitors such as vincristine and paclitaxel. As a lipophilic agent with a low molecular weight, MBZ has the additional advantage of blood-brain barrier permeability. Previous studies suggest that MBZ acts as an inhibitor of vascular endothelial growth factor (VEGF) receptor 2 (VEGFR2), the primary receptor mediating the effects of VEGF. This study reveals the antiangiogenic effect of MBZ in medulloblastoma preclinical mouse models and its encouraging impact on overall survival. In another study Dr. Symons and colleagues examined mebendazole, a medication that is used to treat parasitic pinworms and that in previous studies had been found to be effective in the treatment of glioma tumors. By studying how mebendazole kills isolated tumor cells in the laboratory, they showed that it works in exactly the same way as vincristine. They also found however, that while mebendazole effectively slowed down the growth of glioma tumors, vincristine did not work at all."We were rather surprised to see that vincristine, which is currently used to treat a range of different brain tumors, was totally ineffective in our in vivo glioma model," said Dr. Symons. "In contrast, in the same model, mebendazole performed quite well, most likely because mebendazole crosses the blood-brain barrier and reaches the tumor much better than vincristine. The reason that vincristine may be erroneously believed to be effective for the treatment of brain tumors is that it always has been used in combination with other treatments."Based on the new results -- and due to the fact that vincristine often has severe side effects in comparison to relatively mild reactions to mebendzole -- Dr. Symons and his team are now strongly motivated to initiate clinical trials to test whether vincristine can be exchanged by mebendazole in the treatment of brain tumors."Sometimes innovation can be looking at an existing treatment in a new light," said Kevin J. Tracey, MD, president and CEO of the Feinstein Institute. "This new approach needs to be tested in clinical trials, but with Dr. Symons' new findings we may be closer to a new treatment option that could prolong the lives of the patients suffering from low-grade glioma and other brain tumors." Another study by deWitt et al also came to the same conclusion finding Vincristine ineffective and mebendazole quite effective in various brain tumors.
5. Zardaverine + Quazinone: Nadir M.
showed that subgroups of tumors, within many different cancer types, overexpress PDE3A (mRNA and protein) and that PDE3A expression can predict sensitivity to phosphodiesterase inhibitors.
Searching the Human Protein Atlas database revealed that differential PDE3A expression, as observed in ovarian cancer specimens, is also prevalent in many other cancer types, including colorectal, melanoma, endometrial, testis and urothelial cancers. Their observations suggest that PDE3A has the potential to be both a biomarker of PDE sensitivity and drug target for cancer treatment.
6. Nelfinavir: earlier generation HIV drug with 15 years of safe use data has now been found to have multiple actions against cancer. It's action as monodrug is not as effective as an adjunct. Quoting a review article by Tomas K. "If apoptosis is described as a cascade, then apoptosis stimulator drugs like NFV should be viewed as enhancers of this cascade. An initiator of the cascade is still necessary, for example chemoradiotherapy. After this initial step, apoptosis stimulator drugs increase the amount of cells entering this pathway. This might be one of possible reasons why nelfinavir alone has shown poor results in a clinical trial used as monotherapy.
This does not mean that NFV cannot act as an initiator, but the evidences show that it is prone to be an enhancer of apoptosis rather than an initiator."
This review article also lists all the preclinical trials (Table 2) and clinical trials of Nelfinavir (Table 3):
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4457118/
7. Saquinavir-NO: This is another protease inhibitor like Nelfinavir but may be considered to have equal if not better action against cancers. Listed below are studies which demonstrate it's use and benefit:
ww.ncbi.nlm.nih.gov/m/pubmed/21170266/
https://www.ncbi.nlm.nih.gov/m/pubmed/21270522/https://www.spandidos-publications.com/10.3892/or.2012.1840
8. CH05-10: An analog of Indinavir another PI has also shown broad spectrum anti cancer activity:
https://www.ncbi.nlm.nih.gov/m/pubmed/20946116/
9. Thalidomide + Lenalidomide: Thalidomide was originally developed to treat morning sickness in pregnant women. Its use was stopped because it was found to cause birth defects. Thalidomide is now used as a treatment for cancer, but it must not be taken in pregnancy. A pregnancy prevention programme must be followed during treatment. Thalidomide works in several different ways. It helps the immune system attack and destroy cancer cells. Kill or stop the growth of cancer cells. It affects the chemical messages that cancer cells need to survive. It blocks the development of new blood vessels which cancer cells need to grow and spread. Thalidomide is usually taken with other chemotherapy drugs and steroids as treatment for myeloma. The researchers at Dana Farber Cancer Institute demonstrated that lenalidomide — a more powerful derivative of thalidomide — killed multiple myeloma cells by disabling overactive switches called transcription factors that drive the cells' excessive growth. Transcription factors are proteins that bind to genes and increase their activity, and cancers are often driven by overactivity of these molecular switches. For example, a transcription factor called c-Myc appears to be overactive in many different types of cancer.
10. DMOG dimethyloxalylglycine:
A team of researchers from the U.K. and the U.S. has found that a drug used to study hypoxia can also be used to inhibit glutamine metabolism—a possible means for targeting cancer cells by cutting off their supply line. In their paper published in the journal Nature Chemical Biology. The researchers began their study by noting that a lot of tumors require glutamine to survive—they utilize it in a process called glutaminolysis. A drug called dimethyloxalylglycine (DMOG) might be useful in inhibiting glutamine used by cancer cells. Many types of cancer cells exhibit glutamine addiction. The growing cancer must synthesize nitrogenous compounds in the form of nucleotides and NEAAs. Glutamine is the obligate nitrogen donor. Glutamine’s contribution to amino acid biosynthesis establishes it as a key ingredient for the protein translation needs of cancer cells. A further role for glutamine in cancer cell protein translation stems from observations that a master regulator of protein translation, the mammalian target of rapamycin complex 1 (mTORC1), is responsive to glutamine levels. Glutamine consumption rate of many of the cancer cell lines exceeded the consumption of any other amino acid by ten-fold. Many cancer cell lines could not proliferate in the absence of exogenous glutamine and many could not maintain their viability in the absence of glutamine. Replenishment of the mitochondrial carbon pool by glutamine provides the mitochondria with precursors for the maintenance of mitochondrial membrane potential and for the synthesis of nucleotides, proteins, and lipids.
wide variety of human cancer cell lines have shown sensitivity to glutamine starvation, including those derived from pancreatic cancer, glioblastoma multiforme, acute myelogenous leukemia, colon cancer and small cell lung cancer.
 |
| High Throughput Screening Robot |
11. Blocking Cancer Exosomes:
Tulane University scientists Abdel Mageed, Amrita Dutta, et al used robotic high throughput screening technique to identify approved compounds that could block cancer exosomes. Apparently cancer exosomes are implicated in the spread of cancer. So any drug that blocks cancer exosomes from bring released by cancer cells can be very valuable to cancer patients at all stages. It can also be taken as an adjunct. They screened 4,580 compounds. The lead compounds tipifarnib, neticonazole, climbazole, ketoconazole, and triademenol were validated as potent inhibitors.
12. Slowing down Cancer Metastasis:
I am a fan of young Johns Hopkins scientists Hasini Jayatilika. She and her colleagues discovered that it is not tumour size that triggers metastsis (parts breaking out to form tumours at other site) but it is tumour density that triggers metastasis. I reported about her significant discovery in one of my earlier posts on this blog.
After 7 years of research she demonstrated how after reaching a certain density tumour cells begin to release two proteins Interleukin 6 and Interleukin 8. They tell the new cancer cells that it is getting too crowded separate out and build your own nest at some other site. She observed this after studying the communications between cancer cells. She also discovered two approved drugs known to work on Interleukin receptors that significantly slowed down metastasis:
Tocilizumab a rheumatoid arthritis treatment and Reparixin a potential cancer drug. When combined they seemed to significantly slow down the metastasis.
13. Cimetidine:
It was originally approved/used as a histamine blocker to reduce stomach acid secretion. But since many years multiple actions against cancer has been discovered. One of them is consistent with its previous use: some cancers release a lot of histamine to suppress immune response. Another one is even more startling: cancer cells have ligands Lewis X and Lewis A4 that bind to E-Selectin on endothelial walls for its metastasis. 'Since cimetidine inhibits the expression of E-selectin in blood vessels, cancer cells that are in the bloodstream can't bind to the blood vessels and establish a metastatic tumor. Instead they are eventually eliminated. This would obviously lead to a much better outcome for the patient. Indeed, patients with aggressive colon cancer (Dukes grade C) had a remarkable 84.6% ten year survival rate when treated with cimetidine for one year after surgery compared to a 23.1% ten year survival rate for patients that were not treated with cimetidine as an adjuvant therapy.'
Dr. Michele Morrow has written an article on Cimetidine's various actions against certain cancers like colorectal, gasttic, breast and pancreatic here:
https://www.lifeextension.com/magazine/2002/7/cover_cimetidine/Page-01
14. Clarithromycin:
Dr. Ferreri of San Raffaele Scientific Institute found the following in a human trial of 23 patients with high dose Clarithromycin:
Clarithromycin displays immunomodulatory and antineoplastic properties. As single agent, this macrolide is associated with tumor responses in anecdotal cases of relapsed/refractory extranodal marginal zone lymphoma (rrEMZL). Twenty-three patients were registered (median age 70 years, range 47–88 years; M:F ratio: 0.27) Tolerability was excellent, even among HBV/HCV-positive patients; only two patients had grade >2 toxicity (nausea). Six patients achieved a complete remission and six a partial response (ORR = 52%; 95% confidence interval 32% to 72%). Age, previous treatment and stage did not influence activity. At a median follow-up of 24 (16–33) months, only two patients with responsive disease experienced relapse, with a 2-year progression-free survival of 56 ± 10%; all patients are alive. Gauthier Bouche et al in a review article identified multiple myeloma, lymphoma, chronic myeloid leukaemia (CML), and lung cancer having the highest level of evidence of benefit of Clarithromycin.
15. ReDO Project:
In an article published in ecancer medical sciences by Gauthier Bouche and colleagues they write about the ReDO project in which they use high throughput screening and data from clinical trials to identify approved drugs for repurposing in oncology.
Please do visit their site to learn more. This is a valuable resource for cancer patients and they should take full advantage of it and bring it to the attention of their oncologist if they see any of the identified drugs showing benefit on their cancer. They have so far identified 250 such drugs and compounds out of which they are first focusing on 6 Mebendazole, Nitroglycerin, Cimetidine, Clarithromycin, Diclofenac and Itraconazole. Start with this article:
https://ecancer.org/journal/8/full/442-the-repurposing-drugs-in-oncology-redo-project.php
Then go toReDO website:
http://www.redo-project.org
16. Metformin:
Is a leading oral tablet prescribed to millions of type 2 diabetics over many decades. All cancer patients should consider starting Metformin immediately after diagnosis. Due to its healthspan extension ability all adults above 40 years should consider it as a preventive. It is under phase II and phase III trials for its anti cancer actions. One of its primary actions is inhibition of mTOR1.
The mTOR pathway plays a pivotal role in metabolism, growth and proliferation of cancer cell. Increased levels of circulating insulin/IGF1 and upregulation of insulin/IGF receptor signaling pathways were demonstrated to be involved in the formation of many types of cancer. Metformin was found to reduce insulin level, inhibit insulin/IGF signaling pathways, and modify cellular metabolism in normal and cancer cells. Jacek Kasznicki of Medical University of Lodz and colleagues have written a useful review article in ATM Journal.
Cancer cell under electron microscope
With Syrosingopine:
In another exciting finding published in Cell in 2018 titled 'Lethal combination: Drug cocktail turns of juice to cancer cells' by University of Basel, they discovered that metformin and syrosingopine originally approved as a hypertensive drug made cancer cells die. The combination of the two drugs blocks a critical step in energy production thus leading to an energy shortage, which finally drives cancer cells to "suicide". Cancer cells have high energy demands due to their increased metabolic needs and rapid growth. A limiting factor in meeting this demand is the molecule NAD+, which is key for the conversion of nutrients into energy. "In order to keep the energy-generating machinery running, NAD+ must be continuously generated from NADH," explains Don Benjamin, first author of the study. "Interestingly, both metformin and syrosingopine prevent the regeneration of NAD+, but in two different ways." Many tumor cells shift their metabolism toward glycolysis, which means that they generate energy mainly via the breakdown of glucose to lactate. Since the accumulation of lactate leads to a blockade of the glycolytic pathway, cancer cells eliminate lactate by exporting it from the cell via specific transporters. "We have now discovered that syrosingopine efficiently blocks the two most important lactate transporters and thus, inhibits lactate export," says Benjamin. "High intracellular lactate concentrations, in turn, prevent NADH from being recycled into NAD+."
Because the anti-diabetes drug metformin blocks the second of the two cellular pathways for NAD+ regeneration, combined metformin-syrosingopine treatment results in complete loss of the cell's NAD+ recycling capacity. The depletion of NAD+ in turn leads to cell death, as the cancer cells are no longer able to produce sufficient energy. Thus, pharmacological inhibition of lactate transporters by syrosingopine or other similarly acting drugs can increase the anti-cancer efficacy of metformin and may prove a promising approach to fighting cancer. The former Basel-based company Ciba originally developed syrosingopine for the treatment of hypertension in 1958. The identification of syrosingopine as a dual inhibitor of the two main lactate transporters is an important discovery, as currently there is no pharmacological inhibitor available for one of these two transporters (MCT4). The potential application of syrosingopine in cancer therapy could trigger a second career for this old drug.Then go toReDO website:
http://www.redo-project.org
16. Metformin:
Is a leading oral tablet prescribed to millions of type 2 diabetics over many decades. All cancer patients should consider starting Metformin immediately after diagnosis. Due to its healthspan extension ability all adults above 40 years should consider it as a preventive. It is under phase II and phase III trials for its anti cancer actions. One of its primary actions is inhibition of mTOR1.
The mTOR pathway plays a pivotal role in metabolism, growth and proliferation of cancer cell. Increased levels of circulating insulin/IGF1 and upregulation of insulin/IGF receptor signaling pathways were demonstrated to be involved in the formation of many types of cancer. Metformin was found to reduce insulin level, inhibit insulin/IGF signaling pathways, and modify cellular metabolism in normal and cancer cells. Jacek Kasznicki of Medical University of Lodz and colleagues have written a useful review article in ATM Journal.
With Syrosingopine:
In another exciting finding published in Cell in 2018 titled 'Lethal combination: Drug cocktail turns of juice to cancer cells' by University of Basel, they discovered that metformin and syrosingopine originally approved as a hypertensive drug made cancer cells die. The combination of the two drugs blocks a critical step in energy production thus leading to an energy shortage, which finally drives cancer cells to "suicide". Cancer cells have high energy demands due to their increased metabolic needs and rapid growth. A limiting factor in meeting this demand is the molecule NAD+, which is key for the conversion of nutrients into energy. "In order to keep the energy-generating machinery running, NAD+ must be continuously generated from NADH," explains Don Benjamin, first author of the study. "Interestingly, both metformin and syrosingopine prevent the regeneration of NAD+, but in two different ways." Many tumor cells shift their metabolism toward glycolysis, which means that they generate energy mainly via the breakdown of glucose to lactate. Since the accumulation of lactate leads to a blockade of the glycolytic pathway, cancer cells eliminate lactate by exporting it from the cell via specific transporters. "We have now discovered that syrosingopine efficiently blocks the two most important lactate transporters and thus, inhibits lactate export," says Benjamin. "High intracellular lactate concentrations, in turn, prevent NADH from being recycled into NAD+."
17. Trifluoperazine:
Is approved as an anti-psychotic agent.
Pulloski-Gross et al demonstrated in 2014 that trifluoperazine is responsible for reducing the angiogenic and invasive potential of aggressive cancer cells through dopamine receptor D2 to modulate the b-catenin pathway and propose that trifluoperazine may be used as an antimetastasis chemotherapeutic.
In a screening experiment conducted by Yeh CT et al to target Cancer Stem Cells Trifluoperazine stood out for its action especially along with conventional therapy to stop proliferation of CSCs. In another post on this blog I have mentioned about the danger of drug resistance and remission due to CSCs. The combination of trifluoperazine with either gefitinib or cisplatin overcame drug resistance in lung CSCs. Trifluoperazine inhibited the tumor growth and enhanced the inhibitory activity of gefitinib in lung cancer metastatic and orthotopic CSC animal models. In another in vitro and in vivo study by Kang et el Trifluoperazine potently suppresses proliferation, motility, and invasion of glioblastoma cells in vitro, and tumor growth in in vivoxenograft mouse model. In another study in 2017 by iang et al on two HCC lines they found that
apoptosis was increased and the ability of migration or invasion was found to be impaired by Trifluoperazine. FOXO1 which acts as tumor suppressor on HCC lines expression was increased. Trifluoperazine in vivo could effectively restrict the angiogenesis and tumor growth with reduced expression of VEGF, Bcl-2, and PCNA, and increased the nuclear localization of FOXO1, which indicated its antitumor role in HCC. Terifluoperazine has been recently reported to show a strong anticancer effect on lung cancer, hepatocellular carcinoma, and T-cell lymphoma. Feng et al in 2018 found Trifluoperazine effective in prolonging survival and inducing apoptosis in Triple Negative Breast Cancer that has metastasized to the brain.Chlorpromazine:
Is another anti psychotic drug that has shown action in glioblastoma and colorectal cancer cells.
18. Disulfiram + Copper:
Like Metformin and Syrosingopine every cancer patient should consider taking this combo. Disulfiram also branded as Antabuse is prescribed to deter alchololics from drinking. There has been an amazing case of stage IV breast cancer patient whose cancer at age 38 had spread to her bones. Her doctors stopped all cancer medicine and prescribed her with Disulfiram. She died 10 years later out of a inebriated fall from a window and not cancer. During autopsy they were shocked to find that all her cancer in her bones had melted away leaving very few cancer cells in her morrow. Dr. Jiri Bartek of Danish Cancer Society Research Center Copenhagen and his colleagues in some brilliant work deciphered how Disulfiram killed all types of cancer cells. They showed that disulfiram and its main metabolite, ditiocarb, forms a complex with copper that blocks the machinery that cells use to dispose of misfolded and unneeded proteins. Partly because of the resulting protein buildup, the cancer cells become stressed and die. Bartek’s team also solved another puzzle—why normal cells aren’t harmed by disulfiram, even when patients take it for years. For unclear reasons, the copper metabolite is 10 times more abundant in tumor tissue compared with other tissues, the group found. Bartek and collaborators are now launching trials to test a disulfiram-copper combo as a treatment for metastatic breast and colon cancers and for glioblastoma, a type of brain cancer. Finding a new use for an approved drug is appealing because the compound has already passed safety testing. However, “big pharma probably won’t be interested” in developing disulfiram for cancer because there’s no patent protection on the drug, Bartek says. Still, if the pending clinical trials provide convincing evidence, oncologists could go ahead and prescribe it anyway as an inexpensive treatment. In a study published in Acta Biomaterials Huacheng et al administered Loaded Disulfiram nanoparticle plus copper ions (LDNP/Cu) wherein LDNP is DSF nanoparticle with lactobionic acid, a selective ligand for D-galactose receptor that is effective in targeting cancer cells to one group of mice with metastatic ovarian cancer from human cancer line. Once a week for 3 weeks. After monitoring tumor growth weekly, He and colleagues found that LDNP/Cu was the most effective in impeding tumor growth, and that rapid tumor growth occurred in controls. In addition, the researchers observed numerous tumors in the abdominal cavities of controls but fewer in mice treated with nanoparticles. Researchers evaluated the systemic toxicity of the nanoparticles, in part, via histologic exam of the liver, and found no noticeable differences between the treatment groups. “Altogether, the in vivo data indicate that the LDNP/Cu nanoparticle could be an effective and safe tool for the treatment of advanced ovarian cancer,” the authors concluded. In another study by Lui P et al Disulfiram abolished Cancer Stem Cell characters and completely reversed Paclitaxel and Cisplatin resistance in Triple Negative Breast Cancer cells. Young Min Park et al had success in remarkably slowing down head and neck squamous carcinoma cancer cell lines (FaDu and Hep2) in xenograft mice with Disulfirma and Copper.
19. Fenofibrate:
Since its clinical introduction as a third-generation fibrate in 1975, fenofibrate has been widely used in the treatment of hypercholesterolemia and hyperlipidemia. The lipid-lowering effect of fenofibrate is believed to be mediated through its stimulation of peroxisome proliferator-activated receptor α (PPARα). In addition to its lipid-lowering function, fenofibrate exerts also pleiotropic effects. For instance, fenofibrate was found to not only slow the progression of diabetic retinopathy and other microvascular complications in patients with type 2 diabetes, but also protect against retinopathy, nephropathy, and cardiac pathological changes in type 1 diabetes. Fenofibrate was established to afford myocardial protecttion through its direct effects on the cardiovascular system. Most recently, PPARα-specific agonists were reported to have anticancer effects in a large number of human cancer types, such as acute myeloid leukemia, chronic lymphocytic leukemia, and solid tumors, including those of the liver, ovary, breast, skin, and lungs. Furthermore, fenofibrate inhibited the proliferation of cell lines derived from breast and oral tumors, melanoma, lung carcinoma, glioblastoma, and fibrosarcoma in mouse models. The above is part of an excellent review article by Xin Lian et al published in 2018 in the Journal of Cancer. Here is link you can share with your oncologist:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5950581/
20. Flunarizine:
A drug approved for migraine has shown anti cancer actions in various studies. Dr. Schmeel et al of Center for Integrated Oncology, Bonn in a study had the following results: Flunarizine induced significant apoptotic activity in all tested myeloma and lymphoma cell lines in a dose-dependent manner. Conclusion: Our results reveal a significant selective induction of apoptosis by flunarizine and suggest an in vivo effect against lymphoma and myeloma. It was also found to positively modulate doxorubicin resistance in human colon adenocarcinoma multi drug resisting cells. Researchers at Baylor College of Medicine knew that a protein called Ras were drivers of wide number of cancers. They screened FDA approved drugs that could degrade Ras. Of all the ones they tested Flunarizine showed the best results. In their study published in Scientific Reports in 2018 Chang et al the researchers also tested the effect of flunarizine in a mouse model of triple negative breast cancer and found that it slowed down tumor growth. They also determined that flunarizine promotes N-Ras degradation by enhancing a natural cellular pathway called autophagy.
21. Ribavirin:
A broad spectrum anti-viral drug has shown action against multiple cancers. In a review paper by Dr. Katherine Borden with co-authors in 2010 concludes: Ribavirin targets at least two distinct biochemical entities: eIF4E and IMPDH. Ribavirin clearly targets the oncogenic activity of eIF4E in cell lines, in animal models, and in AML patients. Ribavirin monotherapy led to objective clinical benefit in many of these patients. The effects of ribavirin on the immune system, and whether these are mediated through eIF4E and/or IMPDH, may also play a role in its anti-cancer activities in AML patients. Given that eIF4E is up-regulated in over 30% of cancers, the hope is that ribavirin will become an important component in a wide variety of treatment regimens.
Here is a link to the paper:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2950216/#__ffn_sectitle
In a more recent study of 2017 in xenograft mice model Shen et al showed that that ribavirin inhibited proliferation and induced apoptosis in the thyroid cancer cell lines 8505C and FTC-133. Ribavirin inhibited thyroid cancer growth in a xenograft mouse model. Ribavirin also sensitized thyroid cancer's response to paclitaxel. They concluded that their data clearly demonstrate that ribavirin acts on thyroid cancer cells by inhibiting eIF4E/β-catenin signaling. Our findings suggest that ribavirin has the potential to be repurposed for thyroid cancer treatment and also highlight the therapeutic value of inhibiting eIF4E-β-catenin in thyroid cancer. In another study Ribavirin showed benefit only in some cancers. Researchers investigated the growth inhibitory effects of ribavirin, the cell lines were exposed to different concentrations of ribavirin (10–50 μM) and cell viability was analyzed at 72 h. The results showed that the cell lines were inhibited in a dose-dependent manner although the extent of inhibition was cell line-dependent. The MCF-7 and MDA-436 breast cancer, DU145 prostate carcinoma and D54 glioma cell lines showed increased inhibition whereas the SW480 colon cancer, prostate PC3 and breast MDA-231 cells were less inhibited. HeLa cells showed minimal inhibition even at the highest dose of ribavirin.
22. SPHINX31:
In a new study (2018), Sanger Institute researchers and their collaborators set out to work out how inhibition of SRPK1 gene can kill AML cells and whether it has therapeutic potential in this disease. They first showed that genetic disruption of SRPK1 stopped the growth of MLL-rearranged AML cells and then went on to study the compound SPHINX31, an inhibitor of SRPK1, which was being used to develop an eye drop treatment for retinal neovascular disease – the growth of new blood vessels on the retinal surface that bleed spontaneously and cause vision loss. The team found that the compound strongly inhibited the growth of several MLL-rearranged AML cell lines, but did not inhibit the growth of normal blood stem cells. They then transplanted patient-derived human AML cells into immunocompromised mice and treated them with the compound. Strikingly, the growth of AML cells was strongly inhibited and the mice did not show any noticeable side effects. 23. Tubeimoside I (TBM): Tubeimoside I (TBM) is extracted from the tuber of Bolbostemma paniculatum (Maxim) Franquet (Cucurbitaceae), a traditional Chinese herb previously used in anti-viral or anti-inflammatory treatment.Growing studies have reported its direct cytotoxity in multiple human cancer cells, characterized by mitochondrial damage, endoplasmic reticulum stress, apoptosis and cell cycle arrest. In addition, TBM could sensitize human ovarian cancer cells to cisplatin (CDDP). TBM has been considered as a promising anticancer agent. Cerevical cancer is one of the most aggressive human cancers with poor prognosis due to constant chemoresistance and repeated relapse. Tubeimoside I (TBM) has been identified as a potent antitumor agent that inhibits cancer cell proliferation by triggering apoptosis and inducing cell cycle arrest. In a study by Xuping Fen et al in Cell Death and Disease a Nature publication found that TBM could induce proliferation inhibition and cell death in cervical cancer cells both in vitro and in vivo. Further results demonstrated that treatment with TBM could induce autophagosome accumulation, which was important to TBM against cervical cancer cells. Mechanism studies showed that TBM increased autophagosome by two pathways: First, TBM could initiate autophagy by activating AMPK that would lead to stabilization of the Beclin1-Vps34 complex via dissociating Bcl-2 from Beclin1; Second, TBM could impair lysosomal cathepsin activity and block autophagic flux, leading to accumulation of impaired autophagolysosomes. In line with this, inhibition of autophagy initiation attenuated TBM-induced cell death, whereas autophagic flux inhibition could exacerbated the cytotoxic activity of TBM in cervical cancer cells. Strikingly, as a novel lethal impaired autophagolysosome inducer, TBM might enhance the therapeutic effects of chemotherapeutic drugs towards cervical cancer, such as cisplatin and paclitaxel. 24. Celecoxib + Digoxin: I usually do not like to list anything unless some in vivo results are encouraging. But for this one I have made an exception because the logic sounds viable even in vivo and also because both the drugs are FDA approved their safety has been thoroughly tested. Of course the doctor would make the final decision. Vadim Backman et al at Northwestern discovered the changes of chromatin in cancer cells thanks an imaging technology developed by them called PWS microscopy. Complex
diseases such as cancer, Blackman says do not depend on the behavior of individual genes, but on the complex interplay among tens of thousands of genes. They used PWS to monitor chromatin in cultured cancer cells. They found that chromatin has a specific "packing density" associated with gene expression that helps cancer cells to evade treatments. The analysis revealed that a more heterogeneous and disordered chromatin packing density was related to greater cancer cell survival in response to chemotherapy. A more conservative and ordered packing density, however, was linked to greater cancer cell death in response to chemotherapy. "Just by looking at the cell's chromatin structure, we could predict whether or not it would survive," says Backman. "Cells with normal chromatin structures die because they can't respond; they can't explore their genome in search of resistance. They can't develop resistance." Based on their discovery, the researchers hypothesized that altering the structure of chromatin to make it more orderly could be one way of boosting cancer cells' vulnerability to treatment.On further investigation, the team found that they could modify chromatin's structure by altering electrolytes in the nucleus of cancer cells. The team tested this strategy using two drugs that are already approved by the Food and Drug Administration (FDA): Celecoxib and Digoxin. Celecoxib is currently used for pain relief, while Digoxin is used to treat atrial fibrillation and heart failure. Both drugs, however, are also able to change the packing density of chromatin. The researchers combined these drugs — which they refer to as chromatin protection therapeutics (CPTs) — with chemotherapyand tested them on cancer cells in the laboratory. According to Backman, they witnessed "something remarkable." "Within 2 or 3 days, nearly every single cancer cell died because they could not respond. The CPT compounds don't kill the cells; they restructure the chromatin. If you block the cells' ability to evolve and to adapt, that's their Achilles' heel." Although they say that one has not yet seen whether it works in live environment in vivo but all the cancer cell lines they tried it worked. 25. Diphenyleneiodonium: DPL can inhibit the production of vitamins that feed cancer cells, causing the cells to starve.“Our observation is that DPI is selectively attacking the cancer stem cells, by effectively creating a vitamin deficiency,” said researcher Michael Lisanti, MD, PhD. “In other words, by turning off energy production in cancer stem cells, we are creating a process of hibernation.” DPI stops the reproduction of cancer cells by cutting off their energy source, according to the study. The drug does this without creating the toxic adverse effects that are common with traditional chemotherapies, according to the study. The authors found that DPI had this effect on cancer stem cells, preventing the creation of more cancer cells. When added to a mixed population of cells, DPI sent stem cells into hibernation, according to the study; however, the drug did not fight against “bulk” cancer cells, which do not typically initiate tumor growth within patients, according to the authors. DPI was observed to inhibit more than 90 proteins enzymes from being converted into cellular energy in the mitochondria, according to the study. The lack of energy production deprives cancer cells of vitamin B-12 and riboflavin, which shuts the stem cell down and prevents growth. “It’s extraordinary; the cells just sit there as if in a state of suspended animation,” Dr Lisanti said. The treatment also works by weakening the cell and making it vulnerable to other drugs used to fight cancer, according to Dr Lisanti. “The beauty of this is that DPI makes the cancer stem cells metabolically-inflexible, so they will be highly susceptible to a many other drugs,” he said.
Pulloski-Gross et al demonstrated in 2014 that trifluoperazine is responsible for reducing the angiogenic and invasive potential of aggressive cancer cells through dopamine receptor D2 to modulate the b-catenin pathway and propose that trifluoperazine may be used as an antimetastasis chemotherapeutic.
In a screening experiment conducted by Yeh CT et al to target Cancer Stem Cells Trifluoperazine stood out for its action especially along with conventional therapy to stop proliferation of CSCs. In another post on this blog I have mentioned about the danger of drug resistance and remission due to CSCs. The combination of trifluoperazine with either gefitinib or cisplatin overcame drug resistance in lung CSCs. Trifluoperazine inhibited the tumor growth and enhanced the inhibitory activity of gefitinib in lung cancer metastatic and orthotopic CSC animal models. In another in vitro and in vivo study by Kang et el Trifluoperazine potently suppresses proliferation, motility, and invasion of glioblastoma cells in vitro, and tumor growth in in vivoxenograft mouse model. In another study in 2017 by iang et al on two HCC lines they found that
apoptosis was increased and the ability of migration or invasion was found to be impaired by Trifluoperazine. FOXO1 which acts as tumor suppressor on HCC lines expression was increased. Trifluoperazine in vivo could effectively restrict the angiogenesis and tumor growth with reduced expression of VEGF, Bcl-2, and PCNA, and increased the nuclear localization of FOXO1, which indicated its antitumor role in HCC. Terifluoperazine has been recently reported to show a strong anticancer effect on lung cancer, hepatocellular carcinoma, and T-cell lymphoma. Feng et al in 2018 found Trifluoperazine effective in prolonging survival and inducing apoptosis in Triple Negative Breast Cancer that has metastasized to the brain.Chlorpromazine:
Is another anti psychotic drug that has shown action in glioblastoma and colorectal cancer cells.
18. Disulfiram + Copper:
Like Metformin and Syrosingopine every cancer patient should consider taking this combo. Disulfiram also branded as Antabuse is prescribed to deter alchololics from drinking. There has been an amazing case of stage IV breast cancer patient whose cancer at age 38 had spread to her bones. Her doctors stopped all cancer medicine and prescribed her with Disulfiram. She died 10 years later out of a inebriated fall from a window and not cancer. During autopsy they were shocked to find that all her cancer in her bones had melted away leaving very few cancer cells in her morrow. Dr. Jiri Bartek of Danish Cancer Society Research Center Copenhagen and his colleagues in some brilliant work deciphered how Disulfiram killed all types of cancer cells. They showed that disulfiram and its main metabolite, ditiocarb, forms a complex with copper that blocks the machinery that cells use to dispose of misfolded and unneeded proteins. Partly because of the resulting protein buildup, the cancer cells become stressed and die. Bartek’s team also solved another puzzle—why normal cells aren’t harmed by disulfiram, even when patients take it for years. For unclear reasons, the copper metabolite is 10 times more abundant in tumor tissue compared with other tissues, the group found. Bartek and collaborators are now launching trials to test a disulfiram-copper combo as a treatment for metastatic breast and colon cancers and for glioblastoma, a type of brain cancer. Finding a new use for an approved drug is appealing because the compound has already passed safety testing. However, “big pharma probably won’t be interested” in developing disulfiram for cancer because there’s no patent protection on the drug, Bartek says. Still, if the pending clinical trials provide convincing evidence, oncologists could go ahead and prescribe it anyway as an inexpensive treatment. In a study published in Acta Biomaterials Huacheng et al administered Loaded Disulfiram nanoparticle plus copper ions (LDNP/Cu) wherein LDNP is DSF nanoparticle with lactobionic acid, a selective ligand for D-galactose receptor that is effective in targeting cancer cells to one group of mice with metastatic ovarian cancer from human cancer line. Once a week for 3 weeks. After monitoring tumor growth weekly, He and colleagues found that LDNP/Cu was the most effective in impeding tumor growth, and that rapid tumor growth occurred in controls. In addition, the researchers observed numerous tumors in the abdominal cavities of controls but fewer in mice treated with nanoparticles. Researchers evaluated the systemic toxicity of the nanoparticles, in part, via histologic exam of the liver, and found no noticeable differences between the treatment groups. “Altogether, the in vivo data indicate that the LDNP/Cu nanoparticle could be an effective and safe tool for the treatment of advanced ovarian cancer,” the authors concluded. In another study by Lui P et al Disulfiram abolished Cancer Stem Cell characters and completely reversed Paclitaxel and Cisplatin resistance in Triple Negative Breast Cancer cells. Young Min Park et al had success in remarkably slowing down head and neck squamous carcinoma cancer cell lines (FaDu and Hep2) in xenograft mice with Disulfirma and Copper.
19. Fenofibrate:
Since its clinical introduction as a third-generation fibrate in 1975, fenofibrate has been widely used in the treatment of hypercholesterolemia and hyperlipidemia. The lipid-lowering effect of fenofibrate is believed to be mediated through its stimulation of peroxisome proliferator-activated receptor α (PPARα). In addition to its lipid-lowering function, fenofibrate exerts also pleiotropic effects. For instance, fenofibrate was found to not only slow the progression of diabetic retinopathy and other microvascular complications in patients with type 2 diabetes, but also protect against retinopathy, nephropathy, and cardiac pathological changes in type 1 diabetes. Fenofibrate was established to afford myocardial protecttion through its direct effects on the cardiovascular system. Most recently, PPARα-specific agonists were reported to have anticancer effects in a large number of human cancer types, such as acute myeloid leukemia, chronic lymphocytic leukemia, and solid tumors, including those of the liver, ovary, breast, skin, and lungs. Furthermore, fenofibrate inhibited the proliferation of cell lines derived from breast and oral tumors, melanoma, lung carcinoma, glioblastoma, and fibrosarcoma in mouse models. The above is part of an excellent review article by Xin Lian et al published in 2018 in the Journal of Cancer. Here is link you can share with your oncologist:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5950581/
20. Flunarizine:
A drug approved for migraine has shown anti cancer actions in various studies. Dr. Schmeel et al of Center for Integrated Oncology, Bonn in a study had the following results: Flunarizine induced significant apoptotic activity in all tested myeloma and lymphoma cell lines in a dose-dependent manner. Conclusion: Our results reveal a significant selective induction of apoptosis by flunarizine and suggest an in vivo effect against lymphoma and myeloma. It was also found to positively modulate doxorubicin resistance in human colon adenocarcinoma multi drug resisting cells. Researchers at Baylor College of Medicine knew that a protein called Ras were drivers of wide number of cancers. They screened FDA approved drugs that could degrade Ras. Of all the ones they tested Flunarizine showed the best results. In their study published in Scientific Reports in 2018 Chang et al the researchers also tested the effect of flunarizine in a mouse model of triple negative breast cancer and found that it slowed down tumor growth. They also determined that flunarizine promotes N-Ras degradation by enhancing a natural cellular pathway called autophagy.
21. Ribavirin:
A broad spectrum anti-viral drug has shown action against multiple cancers. In a review paper by Dr. Katherine Borden with co-authors in 2010 concludes: Ribavirin targets at least two distinct biochemical entities: eIF4E and IMPDH. Ribavirin clearly targets the oncogenic activity of eIF4E in cell lines, in animal models, and in AML patients. Ribavirin monotherapy led to objective clinical benefit in many of these patients. The effects of ribavirin on the immune system, and whether these are mediated through eIF4E and/or IMPDH, may also play a role in its anti-cancer activities in AML patients. Given that eIF4E is up-regulated in over 30% of cancers, the hope is that ribavirin will become an important component in a wide variety of treatment regimens.
Here is a link to the paper:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2950216/#__ffn_sectitle
In a more recent study of 2017 in xenograft mice model Shen et al showed that that ribavirin inhibited proliferation and induced apoptosis in the thyroid cancer cell lines 8505C and FTC-133. Ribavirin inhibited thyroid cancer growth in a xenograft mouse model. Ribavirin also sensitized thyroid cancer's response to paclitaxel. They concluded that their data clearly demonstrate that ribavirin acts on thyroid cancer cells by inhibiting eIF4E/β-catenin signaling. Our findings suggest that ribavirin has the potential to be repurposed for thyroid cancer treatment and also highlight the therapeutic value of inhibiting eIF4E-β-catenin in thyroid cancer. In another study Ribavirin showed benefit only in some cancers. Researchers investigated the growth inhibitory effects of ribavirin, the cell lines were exposed to different concentrations of ribavirin (10–50 μM) and cell viability was analyzed at 72 h. The results showed that the cell lines were inhibited in a dose-dependent manner although the extent of inhibition was cell line-dependent. The MCF-7 and MDA-436 breast cancer, DU145 prostate carcinoma and D54 glioma cell lines showed increased inhibition whereas the SW480 colon cancer, prostate PC3 and breast MDA-231 cells were less inhibited. HeLa cells showed minimal inhibition even at the highest dose of ribavirin.
22. SPHINX31:
In a new study (2018), Sanger Institute researchers and their collaborators set out to work out how inhibition of SRPK1 gene can kill AML cells and whether it has therapeutic potential in this disease. They first showed that genetic disruption of SRPK1 stopped the growth of MLL-rearranged AML cells and then went on to study the compound SPHINX31, an inhibitor of SRPK1, which was being used to develop an eye drop treatment for retinal neovascular disease – the growth of new blood vessels on the retinal surface that bleed spontaneously and cause vision loss. The team found that the compound strongly inhibited the growth of several MLL-rearranged AML cell lines, but did not inhibit the growth of normal blood stem cells. They then transplanted patient-derived human AML cells into immunocompromised mice and treated them with the compound. Strikingly, the growth of AML cells was strongly inhibited and the mice did not show any noticeable side effects. 23. Tubeimoside I (TBM): Tubeimoside I (TBM) is extracted from the tuber of Bolbostemma paniculatum (Maxim) Franquet (Cucurbitaceae), a traditional Chinese herb previously used in anti-viral or anti-inflammatory treatment.Growing studies have reported its direct cytotoxity in multiple human cancer cells, characterized by mitochondrial damage, endoplasmic reticulum stress, apoptosis and cell cycle arrest. In addition, TBM could sensitize human ovarian cancer cells to cisplatin (CDDP). TBM has been considered as a promising anticancer agent. Cerevical cancer is one of the most aggressive human cancers with poor prognosis due to constant chemoresistance and repeated relapse. Tubeimoside I (TBM) has been identified as a potent antitumor agent that inhibits cancer cell proliferation by triggering apoptosis and inducing cell cycle arrest. In a study by Xuping Fen et al in Cell Death and Disease a Nature publication found that TBM could induce proliferation inhibition and cell death in cervical cancer cells both in vitro and in vivo. Further results demonstrated that treatment with TBM could induce autophagosome accumulation, which was important to TBM against cervical cancer cells. Mechanism studies showed that TBM increased autophagosome by two pathways: First, TBM could initiate autophagy by activating AMPK that would lead to stabilization of the Beclin1-Vps34 complex via dissociating Bcl-2 from Beclin1; Second, TBM could impair lysosomal cathepsin activity and block autophagic flux, leading to accumulation of impaired autophagolysosomes. In line with this, inhibition of autophagy initiation attenuated TBM-induced cell death, whereas autophagic flux inhibition could exacerbated the cytotoxic activity of TBM in cervical cancer cells. Strikingly, as a novel lethal impaired autophagolysosome inducer, TBM might enhance the therapeutic effects of chemotherapeutic drugs towards cervical cancer, such as cisplatin and paclitaxel. 24. Celecoxib + Digoxin: I usually do not like to list anything unless some in vivo results are encouraging. But for this one I have made an exception because the logic sounds viable even in vivo and also because both the drugs are FDA approved their safety has been thoroughly tested. Of course the doctor would make the final decision. Vadim Backman et al at Northwestern discovered the changes of chromatin in cancer cells thanks an imaging technology developed by them called PWS microscopy. Complex
diseases such as cancer, Blackman says do not depend on the behavior of individual genes, but on the complex interplay among tens of thousands of genes. They used PWS to monitor chromatin in cultured cancer cells. They found that chromatin has a specific "packing density" associated with gene expression that helps cancer cells to evade treatments. The analysis revealed that a more heterogeneous and disordered chromatin packing density was related to greater cancer cell survival in response to chemotherapy. A more conservative and ordered packing density, however, was linked to greater cancer cell death in response to chemotherapy. "Just by looking at the cell's chromatin structure, we could predict whether or not it would survive," says Backman. "Cells with normal chromatin structures die because they can't respond; they can't explore their genome in search of resistance. They can't develop resistance." Based on their discovery, the researchers hypothesized that altering the structure of chromatin to make it more orderly could be one way of boosting cancer cells' vulnerability to treatment.On further investigation, the team found that they could modify chromatin's structure by altering electrolytes in the nucleus of cancer cells. The team tested this strategy using two drugs that are already approved by the Food and Drug Administration (FDA): Celecoxib and Digoxin. Celecoxib is currently used for pain relief, while Digoxin is used to treat atrial fibrillation and heart failure. Both drugs, however, are also able to change the packing density of chromatin. The researchers combined these drugs — which they refer to as chromatin protection therapeutics (CPTs) — with chemotherapyand tested them on cancer cells in the laboratory. According to Backman, they witnessed "something remarkable." "Within 2 or 3 days, nearly every single cancer cell died because they could not respond. The CPT compounds don't kill the cells; they restructure the chromatin. If you block the cells' ability to evolve and to adapt, that's their Achilles' heel." Although they say that one has not yet seen whether it works in live environment in vivo but all the cancer cell lines they tried it worked. 25. Diphenyleneiodonium: DPL can inhibit the production of vitamins that feed cancer cells, causing the cells to starve.“Our observation is that DPI is selectively attacking the cancer stem cells, by effectively creating a vitamin deficiency,” said researcher Michael Lisanti, MD, PhD. “In other words, by turning off energy production in cancer stem cells, we are creating a process of hibernation.” DPI stops the reproduction of cancer cells by cutting off their energy source, according to the study. The drug does this without creating the toxic adverse effects that are common with traditional chemotherapies, according to the study. The authors found that DPI had this effect on cancer stem cells, preventing the creation of more cancer cells. When added to a mixed population of cells, DPI sent stem cells into hibernation, according to the study; however, the drug did not fight against “bulk” cancer cells, which do not typically initiate tumor growth within patients, according to the authors. DPI was observed to inhibit more than 90 proteins enzymes from being converted into cellular energy in the mitochondria, according to the study. The lack of energy production deprives cancer cells of vitamin B-12 and riboflavin, which shuts the stem cell down and prevents growth. “It’s extraordinary; the cells just sit there as if in a state of suspended animation,” Dr Lisanti said. The treatment also works by weakening the cell and making it vulnerable to other drugs used to fight cancer, according to Dr Lisanti. “The beauty of this is that DPI makes the cancer stem cells metabolically-inflexible, so they will be highly susceptible to a many other drugs,” he said.
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| Cancer Stem Cells |
