DISCUSSION Here, we showed that 4-to-5 different classes of FDA-approved antibio

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DISCUSSION

Here, we showed that 4-to-5 different classes of FDA-approved antibiotics can be used to selectively target CSCs, across multiple tumor types. Mechanistically, these antibiotics converge on three main mitochondrial targets, as summarized in Figure 15. Thus, molecular disruption of mitochondrial biogenesis or OXPHOS would be a novel therapeutic strategy for the eradication of CSCs. As a result, our fndings have broad implications for the initiation of new clinical trials, for the re-purposing of antibiotics for the treatment of various cancer types, including “pre-malignant” and advanced metastatic disease. 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,

Figure 9: Pyrvinium pamoate dose-dependently inhibits tumor-sphere formation in MCF7 and T47D cells, two commonly used ER(+) breast cancer cell lines. Pyrvinium pamoate was initially tested over the range of 1 nM to 500 nM. Note that 250 nM and 500 nM were the most effective. (*)p <0.001.
of up to 4-to-6 months or more (200 mg per day). Doxycycline also encourages the growth of normal stem cells, has anti-infammatory properties, and even increases lifespan, in certain experimental contexts [12-14]. Thus, the toxic side effects of anti-cancer therapy would be minimized.
Doxycycline has also been used in human tumor xenografts and other animal models to signifcantly reduce tumor burden and even metastatic cancer cell growth [15- 20]. For example, in pancreatic tumor xenografts (with PANC-1 cells), doxycycline treatment reduced tumor growth by ~80% [20]. 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]. 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].
Our results are consistent with the previous fnding that metformin, a widely used anti-diabetic drug, which functions as a mitochondrial inhibitor, can also be used to selectively target CSCs [21, 22]. 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]. 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.
Our global phenotypic approach to target cancer as a single disease of stemness, may also help to avoid drug resistance. We speculate that genetic changes (oncogenic mutations, amplifcations/deletions, and tumor suppressor loss) all converge on “stemness” in tumor-initiating CSCs (Figure 16), driving tumor recurrence, metastasis and drug resistance. Thus, it would be advantageous to phenotypically target “stemness” directly, instead of targeting individual genetic changes, in different cancer types. This would allow the treatment of cancer in a mutation-independent fashion.
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]. These trials were performed on advanced or treatment-resistant patients with B-cell lymphoma (doxycycline) or lung cancer (azithromycin), respectively [23-26]. For example, in lung cancers, azithromycin signifcantly increased 1-year patient survival from 45% to 75%, an ~1.7-fold increase
[26]. Interestingly, it was noted that even lymphoma patients that were “bacteria-free” benefted from only a 3-week course of doxycycline therapy, and showed complete remission of the disease [27]. These results suggest that the antibiotic’s therapeutic effects were actually infection-independent.
Thus, future clinical trials for testing the effcacy of mitochondrially-targetd antibiotics in multiple cancer types are now clearly clinically warranted. In this regard, a clinical trial with doxycycline in patients with advanced breast cancer and bone metastasis is ongoing: https:// clinicaltrials.gov/ct2/show/NCT01847976. Secondly, a trial of doxycycline in relapsed patients with non- hodgkin’s lymphoma has also been initiated: https:// clinicaltrials.gov/ct2/show/NCT02086591. 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). 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.

Question, discussing section are where the authors discuss the overall findings of their experiments, compare it to other sillar studies, and the overall significance importance of the result. Discuss three difference examples of where the authors accomplish the above.

azithromycin was effective against tumoe-sphere formation in all 10 cell lines tested. describe a class of related semi-synthetic dervanives, that ring siructure, that is characieristic of tetracycline. etracyclines show bacterio-static activity against nearly all acrobie and anaerobic bacteria, inclading both Gram- positive and Gram-negative types. Tetracyclines inhibit protein synthesis by preventing the binding of activated amiecacyl-IRNAs to the A-site on the 30S subunit of bacterial ribosomes As such, they reversibly intubit the addition of sew amino acids to the growing polypeptide chain, during protein synthesis Importanily, the 308 bacterial ribosome is homologous the 285 mitnchondrial he Tetracyelines: Doxycycline provides proof-oF- T Tetracycline is a broad-spectrum antibiotic tha is commonly used for the treatment many bacserial infections, and functions as an inhibitor of peotein syethesis in bacteria. Today, it is mainly used for the treatment of acne. However, the term "tetracyclines" is also used so Tov21G Cels- Ovarian PC3 Cels- Prostate Figure 4: Azithromycin inhibits tumor-sphere formation in eight other cell lines, derived from diverse cancer types. For simplicity, the efficacy of azithromycin was tested at a concentration of 230 uM.00L. (A) ERI-) bresst IMDA-MB-2311 and ovarian cancercell lines ISKOV 3 ES2 21 Gl (B) Lang [A549j prostate IPC31, melanoma [A375], and pancreatic IMLA Pacal www.impactjournals.com/ancotarget 4573

Explanation / Answer

In the above case study, we saw how the antibiotics like Doxycycline, Azithromycin etc play a vital role in cancer treatment. The purpose of this study is to see if women with bone metastases from breast cancer will benefit from the addition of doxycycline to their standard bone-targeted therapy where the adult will be asked to take 100 mg of Doxycycline orally twice a day for 12 weeks.Here are some interesting findings of the author:-

1.

common antibiotics have been shown to eradicate mitochondria in cancer stem cells, inhibiting the growth of certain types of cancerous tumors. All four of the antibiotic classes tested eliminated the cancer stem cells in every test that was performed in the study.

2.

Pyrvinium pamoate dose-dependently inhibits tumor-sphere formation in MCF7 and T47D cells, two commonly used ER(+) breast cancer cell lines. Pyrvinium pamoate was initially tested over the range of 1 nM to 500 nM. Note that 250 nM and 500 nM were the most effective. (*)p <0.001 of up to 4-to-6 months or more (200 mg per day). Doxycycline also encourages the growth of normal stem cells, has anti-inflammatory properties, and even increases lifespan.

3.

in pancreatic tumor xenografts (with PANC-1 cells), doxycycline treatment reduced tumor growth by ~80 %. 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.

4.

metformin, a widely used anti-diabetic drug, which functions as a mitochondrial inhibitor, can also be used to selectively target CSCs. Thus, it would be advantageous to phenotypically target “stemness” directly, instead of targeting individual genetic changes, in different cancer types. This would allow the treatment of cancer in a mutation-independent fashion.

5.

recent clinical trials with doxycycline and azithromycin both show positive therapeutic effects in cancer patients.  in lung cancers, azithromycin significantly increased 1-year patient survival from 45% to 75%, a ~1.7-fold increase. it was noted that even lymphoma patients that were “bacteria-free” benefited from only a 3-week course of doxycycline therapy, and showed complete remission of the disease

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