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Author Topic: The Problem Of Cancer Recurrence  (Read 307 times)

Offline danialthomas

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The Problem Of Cancer Recurrence
« on: April 09, 2021, 04:56:35 pm »
Cancer is a shrewd and highly adaptable disease. It has been outsmarting physicians for an awfully long time. With conventional treatment (chemotherapy, radiation, surgery, targeted therapy, and immunotherapy), the statistics are not good. Of the nearly 2 million people newly diagnosed with cancer last year, over 600,000 of them have already died.
Although treatment outcomes have improved with conventional treatment over the last few decades, there are significant challenges that must be overcome, such as multi-drug resistance, disease progression, metastasis, and seemingly inevitable recurrence. The need for new treatment approaches has never been more urgent.
Why does late-stage cancer recur after complete remission is achieved and there is no evidence of disease? Two big reasons for this are cancer stem cells and senescent cancer cells. If these two cell populations are not dealt with, long-term survival will be difficult to achieve.


Cancer Stem Cells:

In the human body, there are healthy stem cells that help repair and regenerate damaged tissues. Similarly, in tumors, there are cancer stem cells (CSCs) that help repair and regenerate tumors. This subset of cancer cells is also known as tumor-survival cells (TSCs) or tumor-initiating cells (TICs). Cancer stem cells are drug-resistant and remain after each round of chemotherapy to repopulate the tumor with new cancer cells.
Many experts believe that successful eradication of cancer stem cells could change the face of cancer treatment. Not only are cancer stem cells a chief driver of treatment failure, cancer progression, metastasis, and recurrence (often more aggressive), but cancer stem cells may also be the root cause of the original tumor itself. Because of the powerful survival mechanisms of cancer stem cells, chemotherapy, radiation, and surgery are unable to kill them. In fact, conventional therapy may do the opposite and stimulate the proliferation and virulence of cancer stem cells.
Cancer stem cells can migrate and nest in distant sites of the body and remain quiescent (dormant) for months, years, or even decades until the right stimuli come along and awaken them. Conventional therapy can shrink tumors; however, it will not prevent tumor recurrence. Sooner or later, lingering cancer stem cells can form new and often more aggressive tumors from a small number of cells (as few as 100). In other words, being “tumor-free” is not the same as being “cancer-free.” Eradicating tumors is not enough. Cancer stem cells must also be eradicated to achieve long-term survival.
At present, there are no drugs that are FDA-approved to specifically target cancer stem cells; however, the following supplements and repurposed medications have been found to target cancer stem cells by killing them and/or preventing them from entering a dormant and more resistant state:

• Bergamot
• Curcumin
• Doxycycline + azithromycin + vitamin C
• EGCG
• Genistein
• Resveratrol
• Sulforaphane
• Tadalafil


Senescent Cancer Cells:

Besides cancer stem cells, the other problematic cells are senescent cancer cells. Not all cancer cells can be forced into apoptosis (programmed cell death) when treated with chemotherapy, radiation, and hormone-blockers. Instead of dying, many cancer cells simply stop dividing and multiplying and enter a senescent or dormant-like state. This is called senescence-associated growth arrest (SAGA), and while it sounds good, it is accompanied by something bad called senescence-associated secretory phenotype (SASP) in which the senescent cancer cells secrete copious amounts of proinflammatory molecules, protein-degrading compounds, and cancer-promoting growth factors that increase the risk of cancer recurrence.
Again, it is good that senescent cancer cells do not divide and multiply like regular cancer cells, however, in the long run, it is bad because senescent cancer cells do not die and secrete toxic compounds. Furthermore, it has been found that these compounds can stimulate cancer stem cells and promote the adverse effects of chemotherapy. If too many senescent cancer cells accumulate, recurrence of cancer can recur.
At present, there are no drugs that are FDA-approved to specifically target senescent cancer cells; however, the following supplements and repurposed medications have been found to eradicate senescent cells or decrease the toxic secretions of those senescent cells that cannot be eradicated:

• Apigenin
• Dasatinib + quercetin
• Fisetin
• FOXO4-DRI
• Melatonin
• Rapamycin
• Tocotrienols

Please note that this information for educational purposes only. It is not intended or implied to be a substitute for professional medical advice, diagnosis, treatment, and monitoring by your personal physician. Therefore, I cannot give dosages for the above-mentioned supplements and medications. That is for your personal physician to determine after studying the references shown below.

Dr. Daniel Thomas, DO, MS
Mount Dora, Florida


References:

Baar MP, Brandt RMC, Putavet DA, Klein JDD, Derks KWJ, Bourgeois BRM, Stryeck S, Rijksen Y, van Willigenburg H, Feijtel DA, van der Pluijm I, Essers J, van Cappellen WA, van IJcken WF, Houtsmuller AB, Pothof J, de Bruin RWF, Madl T, Hoeijmakers JHJ, Campisi J, de Keizer PLJ. Targeted Apoptosis of Senescent Cells Restores Tissue Homeostasis in Response to Chemotoxicity and Aging. Cell. 2017 Mar 23;169(1):132-147.e16.
Castro-Vega LJ, Jouravleva K, Ortiz-Montero P, Liu WY, Galeano JL, Romero M, Popova T, Bacchetti S, Vernot JP, Londoño-Vallejo A. The senescent microenvironment promotes the emergence of heterogeneous cancer stem-like cells. Carcinogenesis. 2015 Oct;36(10):1180-92.
De Francesco EM, Sotgia F, Lisanti MP. Cancer stem cells (CSCs): metabolic strat¬egies for their identification and eradication. Biochem J. 2018;475(9):1611-1634.
Demaria M, O'Leary MN, Chang J, Shao L, Liu S, Alimirah F, Koenig K, Le C, Mitin N, Deal AM, Alston S, Academia EC, Kilmarx S, Valdovinos A, Wang B, de Bruin A, Kennedy BK, Melov S, Zhou D, Sharpless NE, Muss H, Campisi J. Cellular Senescence Promotes Adverse Effects of Chemotherapy and Cancer Relapse. Cancer Discov. 2017 Feb;7(2):165-176.
Dou Z, Berger SL. Senescence Elicits Stemness: A Surprising Mechanism for Cancer Relapse. Cell Metab. 2018 Apr 3;27(4):710-711.
Fiorillo M, Peiris-Pagès M, Sanchez-Alvarez R, Bartella L, Di Donna L, Dolce V, Sindona G, Sotgia F, Cappello AR, Lisanti MP. Bergamot natural products eradi-cate cancer stem cells (CSCs) by targeting mevalonate, Rho-GDI-signalling and mitochondrial metabolism. Biochim Biophys Acta Bioenerg. 2018 Sep;1859(9):984-996.
Fiorillo M, Tóth F, Sotgia F, Lisanti MP. Doxycycline, Azithromycin and Vitamin C (DAV): A potent combination therapy for targeting mitochondria and eradicating cancer stem cells (CSCs). Aging (Albany NY). 2019 Apr 19;11(8):2202-2216.
Hickson LJ, Langhi Prata LGP, Bobart SA, Evans TK, Giorgadze N, Hashmi SK, Herrmann SM, Jensen MD, Jia Q, Jordan KL, Kellogg TA, Khosla S, Koerber DM, Lagnado AB, Lawson DK, LeBrasseur NK, Lerman LO, McDonald KM, McKenzie TJ, Passos JF, Pignolo RJ, Pirtskhalava T, Saadiq IM, Schaefer KK, Textor SC, Victorelli SG, Volkman TL, Xue A, Wentworth MA, Wissler Gerdes EO, Zhu Y, Tchkonia T, Kirkland JL. Senolytics decrease senescent cells in humans: Preliminary report from a clinical trial of Dasatinib plus Quercetin in individuals with diabetic kidney disease. EBioMedicine. 2019 Sep;47:446-456.
Kim EC, Kim JR. Senotherapeutics: emerging strategy for healthy aging and age-related disease. BMB Rep. 2019;52(1):47-55.
Kirkland JL, Tchkonia T. Senolytic drugs: from discovery to translation. J Intern Med. 2020 Nov;288(5):518-536.
Klutzny, S., Anurin, A., Nicke, B. et al. PDE5 inhibition eliminates cancer stem cells via induction of PKA signaling. Cell Death Dis 9, 192 (2018).
Malavolta M, Pierpaoli E, Giacconi R, Basso A, Cardelli M, Piacenza F, Provinciali M. Anti-inflammatory Activity of Tocotrienols in Age-related Pathologies: A SASPected Involvement of Cellular Senescence. Biol Proced Online. 2018 Nov 20;20:22.
Naujokat C, McKee DL. The “Big Five” Phytochemicals Targeting Cancer Stem Cells: Curcumin, EGCG, Sulforaphane, Resveratrol and Genistein. Curr Med Chem. 2020 Feb 27.
Pernicová Z, Slabáková E, Kharaishvili G, et al. Androgen depletion induces senescence in prostate cancer cells through down-regulation of Skp2. Neoplasia. 2011;13(6):526-536.
Perrott KM, Wiley CD, Desprez PY, Campisi J. Apigenin suppresses the senescence-associated secretory phenotype and paracrine effects on breast cancer cells. Geroscience. 2017 Apr;39(2):161-173.
Selli C, Turnbull AK, Pearce DA, Li A, Fernando A, Wills J, Renshaw L, Thomas JS, Dixon JM, Sims AH. Molecular changes during extended neoadjuvant letrozole treatment of breast cancer: distinguishing acquired resistance from dormant tumours. Breast Cancer Res. 2019 Jan 7;21(1):2.
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Wang R, Yu Z, Sunchu B, Shoaf J, Dang I, Zhao S, Caples K, Bradley L, Beaver LM, Ho E, Löhr CV, Perez VI. Rapamycin inhibits the secretory phenotype of senescent cells by a Nrf2-independent mechanism. Aging Cell. 2017 Jun;16(3):564-574.
Yousefzadeh MJ, Zhu Y, McGowan SJ, Angelini L, Fuhrmann-Stroissnigg H, Xu M, Ling YY, Melos KI, Pirtskhalava T, Inman CL, McGuckian C, Wade EA, Kato JI, Grassi D, Wentworth M, Burd CE, Arriaga EA, Ladiges WL, Tchkonia T, Kirkland JL, Robbins PD, Niedernhofer LJ. Fisetin is a senotherapeutic that extends health and lifespan. EBioMedicine. 2018 Oct;36:18-28.
Yu S, Wang X, Geng P, Tang X, Xiang L, Lu X, Li J, Ruan Z, Chen J, Xie G, Wang Z, Ou J, Peng Y, Luo X, Zhang X, Dong Y, Pang X, Miao H, Chen H, Liang H. Melatonin regulates PARP1 to control the senescence-associated secretory phenotype (SASP) in human fetal lung fibroblast cells. J Pineal Res. 2017 Aug;63(1).
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Located in Mount Dora, Florida, Dr. Thomas is one of the most educated, experienced, and innovative physicians in North America. Over the past 30 years, he has helped people throughout the United States and Canada to prevent and overcome disease, improve their health, slow aging, and increase their lifespan. As an active translational researcher, Dr. Thomas has spent over 35,000 hours poring over the latest scientific discoveries and translating max. discoveries into promising theories

 


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