The Use of Geroprotective Agents (mTOR Inhibitors) in the Treatment of Cancer Patients
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Use of Geroprotective Agents (mTOR Inhibitors) in the Treatment of Cancer Patients M. N. Yurova* Petrov National Medical Research Center of Oncology, St. Petersburg, 197758 Russia *e-mail: [email protected] Received May 14, 2019; revised September 2, 2019; accepted September 23, 2019
Abstract—The review discusses experimental and clinical data from recent decades on the use of geroprotective agents of the mTOR inhibitor group for the main and accompanying treatment of cancer patients. The mTOR protein kinase is an interesting therapeutic target for the treatment of multiple cancers with both mTOR inhibitors themselves (rapamycin and its derivatives) and in combination with inhibitors of other pathways (e.g., metformin). mTOR inhibitors, which are not classical cytostatic agents and do not possess carcinogenic activity, show great promise as independent antitumor agents and in combination with conventional chemotherapy. Keywords: mTOR, rapamycin, rapalog, metformin, geroprotector, carcinogenesis DOI: 10.1134/S2079057020030170
The cytoplasmic protein kinase mTOR is an integral component of the PI3/AKT signaling pathway. It plays a key role in the regulation of cell proliferation and metabolism, autophagy, and a number of functions associated with cell growth and survival [27, 52]. It has been found that mTOR-dependent hyperfunctions, signal stability, hypertrophy, and hypermitogenic excitation in combination with a loss of regenerative potential are markers of cell aging. Cellular senescence in cell culture can be caused by mTOR activation [11, 12]. The mTOR inhibitor rapamycin is the first pharmacological agent shown to increase the mammalian lifespan [25]. Subsequently, this effect has been repeatedly confirmed with various experimental models [5, 6, 8, 36, 62]. It is known that tumor cells are characterized by dysregulation of the PI3/AKT pathway, which makes them more sensitive to mTOR inhibition [7, 22]. Thus, mTOR is an interesting therapeutic target for the treatment of multiple cancers, both with the mTOR inhibitors themselves (rapamycin and its derivatives) and in combination with other pathway inhibitors. It was proven that rapalogs (rapamycin and its analogs) in appropriate concentrations are not toxic drugs: they do not kill cells but instead slow their growth, which is an advantage for anticancer and antiaging agents. mTOR inhibitors can regulate tumor growth directly and indirectly. The direct effect of these factors on cancer cells depends on the concentration of the medicinal agent and certain cellular characteristics. The indirect pathway is based on interaction with the processes necessary for tumor angiogenesis [58].
To date, it has been shown that the use of preparations that reduce mTOR activity exhibits an antitumor effect on neuroendocrine tumors, breast cancer, hepatocellular carcinoma, sarcoma, B-cell lymphoma, etc. [46]. The use of mTOR inhibitors (rapalogs) promoted the remission of TSC tumors and suppresses the development of cutaneous Kaposi’s sarcoma in patients after renal transplantat
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