18.07.2015

Treating cancer using stem cells review

This enormous level of detail and genetic complexity makes it extremely difficult to design new diagnostics and targeted-therapeutics, to achieve the goals of personalized medicine. Instead, an alternative approach would be to focus on what is common between different tumor types, rather than on what is divergent between different cancers. Recently, Tomasetti and Vogelstein showed that the life-time risk of two-thirds of cancers could simply be accounted for by the number of times that a given tissue’s stem cells undergo cell division [8]. Based on this rather simple premise, using unbiased quantitative proteomic profiling [9], we have focused on identifying a global phenotypic property of cancer stem cells (CSCs) that could be targeted across multiple tumor types. To test this hypothesis more directly, here we took advantage of the known side effects of specific classes of antibiotics.
More specifically, the erythromycins and chloramphenicol selectively bind to the large subunit of the mitochondrial ribosome and inhibit mitochondrial biogenesis, by preventing the translation of mitochondrial proteins, mainly related to the mitochondrial OXPHOS complexes (Figure 1A).
Thus, these four large classes of antibiotics all function as known inhibitors of mitochondrial biogenesis in mammalian cells. If mitochondrial biogenesis is indeed required for the propagation of all cancer stem cells, then this new therapeutic approach could be applied across multiple cancer types, perhaps in a mutation independent fashion.
Azithromycin is a macrolide antibiotic that is currently used for the treatment of many types of bacterial infections. As a consequence of these positive findings, we next tested the ability of azithromycin to inhibit tumor-sphere formation in a wide-variety of cell lines derived from many different tumor types, including ER(-) breast cancer, ovarian, lung, pancreatic, and prostate cancer, as well as melanoma (summarized in Table 1).
Figure 3: Azithromycin dose-dependently inhibits tumor-sphere formation in MCF7 and T47D cells, two commonly used ER(+) breast cancer cell lines.
Figure 4: Azithromycin inhibits tumor-sphere formation in eight other cell lines, derived from diverse cancer types. Tetracycline is a broad-spectrum antibiotic that is commonly used for the treatment many bacterial infections, and functions as an inhibitor of protein synthesis in bacteria.
We then tested the ability of doxycycline to inhibit tumor-sphere formation in a broad panel of cancer cell lines derived from many different tumor types (Table 1). Figure 5: Doxycycline dose-dependently inhibits tumor-sphere formation in MCF7 and T47D cells, two commonly used ER(+) breast cancer cell lines. Figure 6: Doxycycline inhibits tumor-sphere formation in eight other cell lines, derived from diverse cancer types.
The glycylcyclines are a relatively new antibiotic class that are highly-related to the tetracyclines. Interestingly, quantitatively similar results were obtained with tigecycline, as compared with doxycycline, showing that it also has the capacity to inhibit tumor-sphere formation, across all 10 cell lines tested. Figure 7: Tigecycline dose-dependently inhibits tumor-sphere formation in MCF7 and T47D cells, two commonly used ER(+) breast cancer cell lines. Figure 8: Tigecycline inhibits tumor-sphere formation in eight other cell lines, derived from diverse cancer types. Pyrvinium is a cyanine dye, which is an FDA-approved anti-helmintic drug, that has been used to treat pinworms, as well as strongyloidiasis in humans. As such, we next tested the ability of pyrvinium pamoate to inhibit tumor-sphere formation in a wide-variety of cell lines derived from many different tumor types (listed in Table 1); we used two concentrations of 250 nM and 500 nM. Figure 9: Pyrvinium pamoate dose-dependently inhibits tumor-sphere formation in MCF7 and T47D cells, two commonly used ER(+) breast cancer cell lines. Figure 10: Pyrvinium pamoate inhibits tumor-sphere formation in eight other cell lines, derived from diverse cancer types. To further assess the efficacy of these four classes of antibiotics, we also determined their effectiveness in inhibiting tumor-sphere formation using two other well-established cell lines. Importantly, azithromycin, doxycycline, and tigecycline are all known to cross the blood-brain barrier, making the treatment of brain cancer with these antibiotics feasible. Figure 11: Four FDA-approved antibiotic classes also inhibit tumor-sphere formation in DCIS and glioblastoma cell lines. Importantly, we observed very limited toxicity, which is consistent with fact that these are well-tolerated antibiotics that are already FDA-approved for patient therapy, but are normally used in the context of infectious disease.
Chloramphenicol is a bacterio-static antibiotic used for the treatment of a number of bacterial infections, which first became available in the late 1940s.
Thus, we chose to evaluate the efficacy of chloramphenicol and determined its ability to inhibit mammo-sphere formation using MCF7 cells, over a range of concentrations from 10 µM to 1 mM. Here, we showed that 4-to-5 different classes of FDA-approved antibiotics can be used to selectively target CSCs, across multiple tumor types. This new therapeutic strategy takes advantage of the manageable side-effects of these antibiotics, which affect eukaryotic mitochondria, although these compounds are currently used for the broad-spectrum treatment of bacterial and parasitic infectious diseases.
In this regard, doxycycline is relatively attractive as a new anti-cancer agent, as it has a long half-life systemically and has been used successfully for the long-term treatment of patients with urinary tract infections (UTI), prostatitis or acne, for extended periods of time, of up to 4-to-6 months or more (200 mg per day). Doxycycline has also been used in human tumor xenografts and other animal models to significantly reduce tumor burden and even metastatic cancer cell growth [15-20]. Our results are consistent with the previous finding that metformin, a widely used anti-diabetic drug, which functions as a mitochondrial inhibitor, can also be used to selectively target CSCs [21, 22]. Our global phenotypic approach to target cancer as a single disease of stemness, may also help to avoid drug resistance. Finally, recent clinical trials with doxycycline and azithromycin (intended to treat cancer-associated infections, but not cancer cells) both show positive therapeutic effects in cancer patients, although their selective effects on eradicating cancer stem cells were not yet known or appreciated [23-26]. Thus, future clinical trials for testing the efficacy of mitochondrially-targetd antibiotics in multiple cancer types are now clearly clinically warranted. A single cell suspension was prepared using enzymatic (1x Trypsin-EDTA, Sigma Aldrich, #T3924), and manual disaggregation (25 gauge needle) to create a single cell suspension.
We thank the University of Manchester for providing start-up funds that contributed to the success of this study. All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License. Researchers at the Memorial Sloan Kettering Cancer Center recently reported that it was possible to repair brain damage caused by radiation therapy for brain cancer by using lab-generated cells derived from human stem cells. Radiation is one of the therapies often used in treating brain cancer patients. However, it can induce significant and irreversible damage to the brain that can lead to deterioration of the quality of life for cancer survivors. The team developed a new strategy where they could transform human stem cells, in the presence of a cocktail of molecules including growth factors, into cells programmed to repair brain injuries — oligodendrocyte progenitor cells. The lab-generated oligodendrocyte progenitor cells where then implanted in rats that had been previously subjected to brain irradiation, and had therefore suffered de-myelination of neurons and presented cognitive deficits.
Patricia holds her PhD in Medical Microbiology and Infectious Diseases from the Leiden University Medical Center in Leiden, The Netherlands.
Disclaimer:Radiation Therapy News is strictly a news and information website about the disease. Cancer comes along as a highly impairing condition letting in certain associated symptoms along. The immune system needs to fight off the cancer cells and make the body come to terms with the tough associations around. Proper medication can be helpful along with chemotherapy but certain natural techniques have to be resorted to in order to provide timely relief to the patients. Including vitamins and minerals in daily use can help regulate the immunity system properly. Copper and selenium needs to be provided alongside in order to enhance the white blood cells. Patients can be well relieved of the conditions as better comfort can be provided on using some of the best herbal options available. Though not contagious the microorganisms involved can often thrive and grow well in adverse conditions. Graviola comes along as a natural fruit or herb which has many positive aspects and benefits over the body. Graviola stems the growth of the malignant cells thus rendering them benign at places and also by enhancing the immune response of the body.
Bladder infections can lead to cancerous attributes which in turn can be negated on using garlic in the form of pastes by adding this to the corresponding elements including peppermint. London: A team including an Indian-origin researcher Aravind Vijayaraghavan from the University of Manchester has used graphene to target and neutralise cancer stem cells while not harming other cells. This new development opens up the possibility of preventing or treating a broad range of cancers using a non-toxic material. With lead researcher professor Michael Lisanti, Vijayaraghavan has shown that graphene oxide, a modified form of graphene, acts as an anti-cancer agent that selectively targets cancer stem cells (CSCs). The team prepared a variety of graphene oxide formulations for testing against six different cancer types - breast, pancreatic, lung, brain, ovarian and prostate. The flakes inhibited the formation of tumour sphere formation in all six types, suggesting that graphene oxide can be effective across all, or at least a large number of different cancers, by blocking processes which take place at the surface of the cells. The researchers suggest that, used in combination with conventional cancer treatments, this may deliver a better overall clinical outcome. Promising cures for blood-related diseases, such as leukemia and lymphoma, hematopoietic stem cells (HSCs) have been heavily researched for decades. It is now not only better understood how HSCs from a donor animal can save a lethally irradiated recipient animal, but how HSCs can be used in many other medical applications as well. Hematopoietic stem cells give rise to two major progenitor cell lineages, myeloid and lymphoid progenitors (Regenerative Medicine, 2006). When checked, Shutterstock's safe search screens restricted content and excludes it from your search results. The emerging picture is that while a few driver-mutations are common to certain specific cancer sub-types, each patient’s tumor is fairly unique in its complexity of genetic changes and that several divergent cancer cell clones may also co-exist, within a single tumor [1-5].


This is consistent with the idea that during aging, somatic mutations may accumulate in tissue stem cells, driving the formation of cancer stem cells [8]. We have identified this property as a strict dependence on mitochondrial biogenesis, for the anchorage-independent clonal expansion and survival of the CSC population. Thus, future clinical trials for testing the efficacy of these mitochondrially-targeted antibiotics, in multiple cancer types, are now clearly clinically warranted. For this purpose, we characterized the proteome of mammo-spheres derived from two different ER(+) breast cancer lines, specifically MCF7 and T47D cells [9]. Similarly, the tetracyclines and glycylcyclines both bind with high affinity to the small subunit of the mitochondrial ribosome and inhibit mitochondrial biogenesis as well (Figure 1A).
In essence, we would be treating cancer based instead on a common global phenotypic property that is characteristic of cancer stem cells, allowing this approach to be more broadly applied perhaps to any cancer type (Figure 2). Recently, using unbiased proteomics analysis, we showed that mitochondrial proteins were highly upregulated in MCF7 and T47D tumor-spheres, as directly compared with monolayer cells.
One idea is that we could potentially treat cancer as a single disease, if we could identify a global phenotypic characteristic that is conserved across multiple cancer types. Azithromycin is a derivative of erythromycin, and is generally more potent and is more slowly eliminated than erythromycin, allowing infections to be treated relatively quickly, over 3-to-5 days.
For this purpose, azithromycin was tested for its ability to inhibit mammo-sphere formation using MCF7 and T47D cells, over a range of concentrations.
For simplicity, the efficacy of azithromycin was tested at a concentration of 250 µM. It was first approved by the FDA in 1955 for the treatment of enterobiasis, and is known to act as an inhibitor of mitochondrial oxidative phosphorylation (OXPHOS), under both normoxia and hypoxic conditions. Interestingly, in both MCF7 and T47D cells, pyrvinium pamoate inhibited mammo-sphere formation with an IC-50 between ~10-to-50 nM (Figure 9). Figure 10 (panels A and B) illustrates that pyrvinium pamoate inhibited tumor-sphere formation across the entire cell line panel; pyrvinium pamoate was effective against tumor-sphere formation in all 10 cell lines tested, in the nano-molar range. For simplicity, the efficacy of pyrvinium pamoate was tested at a concentration of 250 nM and 500 nM. Thus, our approach can also be used to target both pre-malignant lesions, such as DCIS, or even the most invasive and aggressive cancer types, such as glioblastoma.
Note that there was little or no toxicity observed in MCF7 cell monolayers or hTERT-BJ1 fibroblasts, over this entire range (Figure 12, panels A and B).
Importantly, there was little or no toxicity observed in MCF7 cell monolayers or hTERT-BJ1 fibroblasts (Figure 13, panels A and B). Interestingly, in MCF7 cells, chloramphenicol inhibited mammo-sphere formation with an IC-50 of ~200 µM (Figure 14). We determined the ability of chloramphenicol to inhibit mammo-sphere formation using MCF7 cells, over a range of concentrations from 10 µM to 1 mM.
Mechanistically, these antibiotics converge on three main mitochondrial targets, as summarized in Figure 15. Doxycycline also encourages the growth of normal stem cells, has anti-inflammatory properties, and even increases lifespan, in certain experimental contexts [12-14]. For example, in pancreatic tumor xenografts (with PANC-1 cells), doxycycline treatment reduced tumor growth by ~80% [20].
Metformin functionally inhibits OXPHOS by targeting complex I of the electron transport chain and can even induce lactic acidosis, as a lethal side effect [21, 22].
These trials were performed on advanced or treatment-resistant patients with B-cell lymphoma (doxycycline) or lung cancer (azithromycin), respectively [23-26]. The five-classes of antibiotics that we tested are summarized here, along with their three corresponding molecular targets, which all converge on mitochondrial biogenesis or OXPHOS.
Girotti MR, Lopes F, Preece N, Niculescu-Duvaz D, Zambon A, Davies L, Whittaker S, Saturno G, Viros A, Pedersen M, Suijkerbuijk BM, Menard D, McLeary R, Johnson L, Fish L, Ejiama S, Sanchez-Laorden B, Hohloch J, Carragher N, Macleod K, Ashton G, Marusiak AA, Fusi A, Brognard J, Frame M, Lorigan P, Marais R, Springer C. Degli Esposti M, Chouaia B, Comandatore F, Crotti E, Sassera D, Lievens PM, Daffonchio D, Bandi C. Ferreri AJ, Dolcetti R, Magnino S, Doglioni C, Cangi MG, Pecciarini L, Ghia P, Dagklis A, Pasini E, Vicari N, Dognini GP, Resti AG, Ponzoni M.
Ferreri AJ, Ponzoni M, Guidoboni M, De Conciliis C, Resti AG, Mazzi B, Lettini AA, Demeter J, Dell’Oro S, Doglioni C, Villa E, Boiocchi M, Dolcetti R.
Ferreri AJ1, Ponzoni M, Guidoboni M, Resti AG, Politi LS, Cortelazzo S, Demeter J, Zallio F, Palmas A, Muti G, Dognini GP, Pasini E, Lettini AA, Sacchetti F, De Conciliis C, Doglioni C, Dolcetti R. After radiation therapy, the progenitor cells that would eventually evolve to generate the protective myelin coating surrounding neurons are lost or significantly reduced, and it is currently not possible to restore these cells.
This strategy was successfully accomplished with both human embryonic stem cells and induced pluripotent stem cells from the skin. Remarkably, rats treated with these specific human progenitor cells re-acquired their cognitive and motor coordination functions that were lost after exposure to radiation.
She has studied Applied Biology at Universidade do Minho and was a postdoctoral research fellow at Instituto de Medicina Molecular in Lisbon, Portugal.
Some of the most frightening aspects which bother the patients are the impaired health conditions along with a weakened immunity system.
The better techniques can be used by adding these to the daily schedule via better health conditions.
Green tea and chamomile can be the most suited options for relieving the patients of the associated discomfort. It can ably decrease the toxin concentration in the body and can help treat the cancerous cells with considerable effects. The method of application remains simple as this can be sued as powdered forms or can be extracted in the form of juices or concoctions mixed with water. Regular supplementation with this can yield rewarding results. This soothes the affected area and enhances the urinating capacity of the same making for a great option in providing ready relief to patients.
It can readily enter or attach to the surface of cells, making it a candidate for targeted drug delivery," Vijayaraghavan explained. Cancer control is frequently short lived, even when these drugs are proven to be effective. They further concluded that these somatic mutations accounted for more cancer cases than either inherited genetic disease or specific environmental risk factors. Overall, the use of generic antibiotics for anti-cancer therapy should significantly reduce the costs of patient care, making treatment more accessible in the developing world. If successful, these FDA-approved antibiotics could then be re-purposed for the treatment of cancer, to achieve the eradication or more effective elimination of cancer stem cells (Figure 1B). Thus, we set out to test the hypothesis that tumor-sphere formation was strictly dependent on mitochondrial biogenesis. Figure 4 (panels A and B) directly shows that azithromycin inhibited tumor-sphere formation in these 8 additional well-established cell lines, representing 6 different cancer types. Figure 6 (panels A and B) directly shows that doxycycline inhibited tumor-sphere formation in all of these well-established cell lines. They have essentially the same mechanism of action as the tetracyclines, as they prevent bacterial protein synthesis. Interestingly, in both MCF7 and T47D cells, tigecycline inhibited mammo-sphere formation with an IC-50 between 10 and 25 µM (Figure 7). The other was derived from one of the most malignant and aggressive tumor types, glioblastoma (brain cancer; U-87 MG). Note that all four antibiotics classes inhibit tumor-sphere formation, in both DCIS and glioblastoma cell lines. Interestingly, 500 nM pyrvinium pamoate reduced MCF7 mammosphere formation by >99% (Figure 9). Like the eyrthromycins and the tetracyclines, it functions as an inhibitor of protein synthesis, by binding to the 50S bacterial ribosomal subunit, thereby inhibiting peptide bond formation.
As such, we have now shown that four independent antibiotic inhibitors of mitochondrial biogenesis (azithromycin, doxycycline, tigecycline, and chloramphenicol) all effectively inhibit mammo-sphere formation. Interestingly, in MCF7 cells, chloramphenicol inhibited mammo-sphere formation with an IC-50 of ~200 µM. Thus, molecular disruption of mitochondrial biogenesis or OXPHOS would be a novel therapeutic strategy for the eradication of CSCs. In a xenograft model of breast cancer bone metastasis (with MDA-MB-231 cells), doxycycline treatment reduced bone and bone-associated soft-tissue tumor mass by >60% and ~80%, respectively [19].
As a result, the use of antibiotics, such as doxycycline, may provide a safer and far more effective alternative to anti-cancer therapy with metformin. For example, in lung cancers, azithromycin significantly increased 1-year patient survival from 45% to 75%, an ~1.7-fold increase [26]. Sotgia were supported by funding schemes from the European Union (ERC Advanced Grant), Breakthrough Breast Cancer (BBC), and the Manchester Cancer Research Centre (MCRC). Paradox-Breaking RAF Inhibitors that Also Target SRC Are Effective in Drug-Resistant BRAF Mutant Melanoma. Variation in cancer risk among tissues can be explained by the number of stem cell divisions. Doxycycline is anti-inflammatory and inhibits staphylococcal exotoxin-induced cytokines and chemokines. Anti-invasion and anti-tumor growth effect of doxycycline treatment for human oral squamous-cell carcinoma--in vitro and in vivo studies.


Interactions of doxycycline with chemotherapeutic agents in human breast adenocarcinoma MDA-MB-231 cells.Anticancer Drugs.
Metformin: an emerging new therapeutic option for targeting cancer stem cells and metastasis.
Metformin selectively targets cancer stem cells, and acts together with chemotherapy to block tumor growth and prolong remission. Long-term outcomes of first-line treatment with doxycycline in patients with previously untreated ocular adnexal marginal zone B cell lymphoma.
Regression of ocular adnexal lymphoma after Chlamydia psittaci-eradicating antibiotic therapy.
Azithromycin enhances the favorable results of paclitaxel and cisplatin in patients with advanced non-small cell lung cancer. Bacteria-eradicating therapy with doxycycline in ocular adnexal MALT lymphoma: a multicenter prospective trial. This protective myelin coating is generated by oligodendrocytes, which are vital for the support, protection, and repair of brain neurons. Jinghua Piao showed that stem cells could be used as a tool to restore destroyed oligodendrocyte progenitor cells.
In terms of safety, the team found that none of the rats developed any kind of inappropriate cell types or brain tumors. Her work has been focused on molecular genetic traits of infectious agents such as viruses and parasites. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Be it animals or the humans bladder cancer comes around as a painful and uncomfortable option for the patients.
These need to be consumed just before going off to the bed and letting the body strengthen itself over a substantial period of time.
Over the years this fruit has gained precedence owing to the easy availability coupled with the high end therapeutic values attached.
For example, the BRAF inhibitor vemurafenib is approved for the treatment of patients whose melanoma harbors the V600E mutation, which is thought to be a driver mutation [6, 7 ]. These findings are consistent with the idea that cancer stem cells are anabolic and that they may require mitochondrial biogenesis for their survival and proliferative expansion [9]. Interestingly, several known classes of FDA-approved antibiotics function as inhibitors of mitochondrial biogenesis, which results in manageable side-effects.
This global phenotypic property appears to be functionally dependent on increased mitochondrial biogenesis. Thus, azithromycin was effective against tumor-sphere formation in all 10 cell lines tested. Tetracyclines show bacterio-static activity against nearly all aerobic and anaerobic bacteria, including both Gram-positive and Gram-negative types. Thus, doxycycline was effective against tumor-sphere formation in all 10 cell lines tested, across 6 different cancer types. Both tetracyclines and glycylcyclines bind to the 30S bacterial ribosomal subunit, thereby inhibiting the binding of a given aminoacyl-tRNA to the A-site of the ribosome. For simplicity, we used a single concentration of 50 µM, in all eight other cell lines, which significantly inhibited tumor-sphere formation (Figures 8). Thus, there is no toxicity for MCF7 cell monolayers or normal fibroblasts at a concentration that nearly completely eliminates CSC expansion (and even at 10X times higher). As such, there is little or no toxicity for MCF7 cell monolayers or normal fibroblasts at a concentration that eliminates CSC expansion (and even at 10X times higher). Pyrvinium pamoate was tested over the range of 500 nM to 5 µM, with little or no effects on cell viability. More specifically, it inhibits peptidyl-transferase activity, preventing protein chain elongation.
However, chloramphenicol was the least potent of the mitochondrial inhibitors that we tested.
However, its anti-cancer activity was attributed to the inhibition of matrix-metalloproteinases (MMPs), rather than the targeting of mitochondrial biogenesis, and doxycycline has not been previously implicated in the selective eradication of cancer stem cells [15-20]. Interestingly, the A375 human melanoma cell line harbors the B-RAF(V600E) mutation and we showed that CSCs derived from this cell line are highly-sensitive to all four of the antibiotics that we tested (azithromcyin, doxycycline, tigecycline, and pyrvinium pamoate).
This would allow the treatment of cancer as a single disease of stemness, in a mutation-independent fashion.
Ubaldo Martinez-Outschoorn was supported by the National Cancer Institute (NCI) of the National Institutes of Health (NIH), under Award Number K08 CA -175193-01A1. Stem cells are undifferentiated cells capable of differentiating into different specialized cell types, like the skin, bone, muscle, etc. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Lisanti1,2 1 The Breakthrough Breast Cancer Research Unit, Institute of Cancer Sciences, University of Manchester, UK 2 The Manchester Centre for Cellular Metabolism (MCCM), Institute of Cancer Sciences, University of Manchester, UK 3 The Moor Allerton Preparatory School, Didsbury, Manchester, UK 4 Departments of Pathology and Medicine, The Albert Einstein College of Medicine, Bronx, NY, USA 5 The Kimmel Cancer Center, Philadelphia, PA, USA * These authors contributed equally to this study and should be considered as co-first authors ** provided the initial idea for this study Correspondence: Michael P.
However, after treatment with vemurafenib, cancer progression occurs within six months in the vast majority of these patients with V600E mutations [6, 7]. Azithromycin directly binds to the 50S subunit of the bacterial ribosome, and specifically inhibits the translation of mRNA species into protein.
Tetracyclines inhibit protein synthesis by preventing the binding of activated aminoacyl-tRNAs to the A-site on the 30S subunit of bacterial ribosomes.
Importantly, it appears that glycylcyclines bind more tightly to the ribosome, than the tetracyclines. We used this approach to further validate that mitochondrial function was indeed critical for the survival and propagation of cancer stem cells. Similarly, in mammalian cells, chloramphenicol behaves an inhibitor of mitochondrial biogenesis.
These results suggest that the antibiotic’s therapeutic effects were actually infection-independent. As such, additional cellular studies, and new clinical trails in melanoma patients with B-RAF mutations, may be indicated, to explore the use of antibiotics. All experiments were performed in triplicate, three times independently, such that each data point represents the average of 9 replicates. Never disregard professional medical advice or delay in seeking it because of something you have read on this website. Erythromycins and chloramphenicol target the large mitochondrial ribosome, while tetracyclines and glycylcyclines target the small mitochondrial ribosomes, because of conserved similarities with bacterial ribosomes. As such, they reversibly inhibit the addition of new amino acids to the growing polypeptide chain, during protein synthesis.
We searched for a global phenotypic characteristic that was highly conserved among cancer stem cells, across multiple tumor types, to provide a mutation-independent approach to cancer therapy. In fact, many of the bacterial ribosomal subunits have directly-related mitochondrial homologues in eukaryotic cells. Importantly, the 30S bacterial ribosome is homologous the 28S mitochondrial ribosome, accounting for the manageable side-effects of the tetracyclines. The structures of erythromycin (a) and tetracycline (b) are shown, along with pyrvinium pamoate (c). As a consequence, tetracycline-based antibiotics are inhibitors of mitochondrial biogenesis. Using this approach, we identified a conserved phenotypic weak point – a strict dependence on mitochondrial biogenesis for the clonal expansion and survival of cancer stem cells. Here, we tested the hypothesis that these different classes of FDA-approved antibiotics could be re-purposed for the targeting of mitochondrial biogenesis and the eradication of cancer stem cells. Doxycycline is a tetracycline-derivative with markedly improved efficacy and stability, which was first FDA-approved in the late 1960s, nearly 50 years ago now. Based on this analysis, we now show that 4-to-5 different classes of FDA-approved drugs can be used to eradicate cancer stem cells, in 12 different cancer cell lines, across 8 different tumor types (breast, DCIS, ovarian, prostate, lung, pancreatic, melanoma, and glioblastoma (brain)). These five classes of mitochondrially-targeted antibiotics include: the erythromycins, the tetracyclines, the glycylcyclines, an anti-parasitic drug, and chloramphenicol. Functional data are presented for one antibiotic in each drug class: azithromycin, doxycycline, tigecycline, pyrvinium pamoate, as well as chloramphenicol, as proof-of-concept. Importantly, many of these drugs are non-toxic for normal cells, likely reducing the side effects of anti-cancer therapy. Thus, we now propose to treat cancer like an infectious disease, by repurposing FDA-approved antibiotics for anti-cancer therapy, across multiple tumor types. These drug classes should also be considered for prevention studies, specifically focused on the prevention of tumor recurrence and distant metastasis. Finally, recent clinical trials with doxycycline and azithromycin (intended to target cancer-associated infections, but not cancer cells) have already shown positive therapeutic effects in cancer patients, although their ability to eradicate cancer stem cells was not yet appreciated.



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