Mikhail V Blagosklonny

..Here, we discuss the relationship between aging and cancer, the mechanism of metformin action, and the prospects of using this compound for life span extension in humans...

..In a broader perspective, this shows how selectivity may be achieved by targeting a non-cancer-specific target, such as histone deacetylases, in the presence of a cancer-specific alteration, such as mutant p53...

..I discuss that these arguments actually support a new theory. Are any questions remaining? And might accumulation of molecular damage still play a peculiar role in aging?..

..Can cancer prevention be explained by direct targeting of cancer cells? Or does rapamycin prevent cancer indirectly through slowing down the aging process? Increasing evidence points to the latter scenario...

..Here I introduce the notion of benevolent diabetes and discuss whether starvation-like effects of chronic high dose treatment with rapamycin are an obstacle for its use as an anti-aging drug...

..At the same time this advance could save Medicare as we know it. Here I discuss how anti-aging interventions could solve otherwise intractable political problems without tax increases or curtailment of health care benefits...

..But can gerossuppression suppress tumors?..

..Also, several therapeutic paradigms can be reassessed, including the role of cellular senescence in cancer therapy...

..Preclinical and clinical studies demonstrated the therapeutic effects of rapamycin in diverse age-related diseases. One simple reason why a single drug is indicated for so many age-related diseases is that it inhibits the aging process...

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..National Cancer Institute has announced 24 provocative questions on cancer. Here I try to answer some of them by linking the dots of existing knowledge...

..If rapamycin is a CR-mimetic, no wonder it may, in certain models, induce "hunger diabetes." But will rapamycin prevent true type II diabetes? Here are some answers...

..I also discuss how random molecular damage, via rounds of multiplication and selection, brings about non-random hallmarks of cancer...

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..We discuss that Mdm antagonists could be used in combination with chemotherapy to reversibly arrest normal cells, thus protecting them during chemotherapy of cancer (cyclotherapy)...

..How can growth inhibitors suppress senescence? May these aging-suppressants decelerate organismal aging? To answer these questions, we need to reconsider the meaning of aging...

..Therefore in humans the effect of CR may be somewhat blunted. Still how much does CR extend human lifespan? And could this extension be surpassed by gerosuppressants such as rapamycin?..

..Here I discuss evidence for and against the ROS theory. Remarkably, even supporting evidence has an alternative explanation, consistent with the model that aging is driven by the TOR (target of rapamycin) signaling pathway...

..I also discuss other potential anti-aging agents (calorie restriction, metformin, resveratrol and sirtuins) and their targets, interference with the TOR pathway and combination with antioxidants...

..Retrospective analysis of clinical data reveals that inhibitors of TOR prevent cancer in humans. This article envisions a potential clinical use of TOR inhibitors in order to slow aging and delay cancer...

..On the basis of the hypothesis that insensitivity to stimuli is in part due to hyperactivation of the target of rapamycin (TOR), this article suggests a means of pharmacologic rejuvenation of stem cells and wound-healing cells...

..Here I discuss restrictive combinations of currently available drugs that could be tested in clinical trials. Could then these combinations cure cancer today? And what does 'cure' really mean? This article suggests the answer...

..In theory, pharmacologic inhibitors of the TOR pathway may reverse accumulation of defective mitochondria, while also inhibiting the aging process...

..This has important application not only for antibacterial therapy but also for cancer therapy: to control cancer with lesser side effects and to eliminate drug-resistant cancer cells, while sparing sensitive normal cells...

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..Enormous 'pre-published' databases coupled with Google-like search engines can change the structure of scientific research, and shrinking funding will make this inevitable...

..The emerging message in 2009 is that aging is not random but determined by a genetically-regulated longevity network and can be decelerated both genetically and pharmacologically...

..I discuss why slow aging is manifested as postponed (healthy) aging, why the rate of deterioration is independent from aging and also entertain hypothetical use of rapamycin in different eras as well as the future of human longevity...

..One prediction remains to be confirmed: rapamycin will become the cornerstone of anti-aging therapy in our life time...

..Early in life the TOR pathway drives developmental program, which persists later in life as an aimless quasi-program of aging and age-related diseases...

..Also, the relation between cancer and senescence is distorted. Here I discuss why the link between arrest and senescence is semi-coincidental and how senescence is related to aging and cancer...

..By knowing the mechanisms of cell cycle arrest, death and senescence, we can design "rainbow combinations" that obediently kill or spare desired cells. Knowledge is power...

..This quasi-program causes over-activation of female reproductive system, which is very vulnerable to over-activation. Mechanisms of aging and menopause are discussed...

..Thus, the nutrient-sensing and growth-promoting TOR signaling pathway may provide a molecular link between growth and aging that is universal from yeast to human...

..Here I discuss four potential scenarios, comparing progeria with both normal and accelerated aging. This reveals further indications of rapamycin both for accelerated aging in obese and for progeria...

..Hormesis B includes ischemic preconditioning and, in part, physical exercise, heat shock, hypoxia and medical interventions...

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..We conclude that induction of p53 does not activate the senescence program in quiescent cells. In cells with induced p53, re-activation of mTOR by serum stimulation causes senescence, as an equivalent of cellular growth...

..Inhibition of TOR partially prevented senescent phenotype caused by DOX. Thus growth stimulation coupled with cell cycle arrest leads to senescence, whereas quiescence (a condition with inactive TOR) prevents senescence...

..We conclude that status of the mTOR pathway can determine, at least in part, the choice between senescence and quiescence in p53-arrested cells...

..Thus, in normal and cancer cell lines, hypoxia suppresses geroconversion caused by diverse stimuli. Physiological and clinical implications of the present findings are discussed...

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..This problem also complicates the study of senescence caused by minimal levels of p21 that are capable to arrest a few cells...

..Taken together this suggests that (a) simultaneous activation of PI-3K and MEK is required to ensure cellular senescence and (b) U0126 and LY294002 suppress senescence via the rapamycin-sensitive pathway...

..Thus, in spite of its ability to induce cell cycle arrest, p53 can act as a suppressor of cellular senescence...

..When p21 was switched off, competent cells, by resuming proliferation, became progressively less hypertrophic. Preservation of proliferative potential is a sensitive and quantitative measure of suppression of mTOR-driven senescence...

..During cell cycle arrest, rapamycin transformed the irreversible arrest into a reversible condition. Our data demonstrate that senescence can be pharmacologically suppressed...

..These results indicate that p21 acts as a negative regulator of p53 stability in different cell types. p53 regulation by p21 may provide a negative regulatory loop that limits p53 induction...

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..In addition, rapamycin decreased the incidence of spontaneous tumors. This observation may have applications in management of Li-Fraumeni syndrome patients characterized by heterozygous mutations in the p53 gene...

..Prolonged hypertrophic arrest culminates in cell senescence. This review discusses that quiescence and senescence are two opposite, mutually exclusive conditions and that cell senescence can be reversed and prevented...

..In contrast, true CSCs are not only a difficult, but also an insufficient and perhaps even an unnecessary therapeutic target, especially in advanced malignancies...

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..We conclude that low p53 levels during prolonged cell cycle arrest tend to cause senescence, whereas high levels of p53 tend to cause either quiescence or cell death...

..If the group is large, then the anti-aging effect could be validated in a couple of years. Startlingly, retrospective analysis of clinical and preclinical data reveals four potential anti-aging modalities...

..Therefore, the effects of hypoxia on the oxygen-sensing mTOR pathway and geroconversion are cell type-specific. We also briefly discuss replicative senescence, organismal aging and free radical theory...

..We discuss that although CS does not mimic organismal aging, the same signal transduction pathways that drive CS also drive aging...

..The failure to limit mTOR-dependent induction of HIF-1 may contribute to age-related macular degeneration and diabetic retinopathy, suggesting rapamycin for prevention of these age-related diseases...

..Our data demonstrate that water soluble Rapatar micelles represent safe, convenient and efficient form of rapamycin suitable for a long-term treatment and that Rapatar may be considered for tumor prevention...

..And this is exactly what Avastin does (by blocking VEGF). While chemotherapy inhibits angiogenesis, Avastin abrogates the reactive resistance, sensitizing both endothelial and cancer cells to therapy...

..But under hypoxia, HIF-1alpha accumulates and transcriptionally activates its own degradation that is independent from the PHD/VHL pathway...

..We suggest that, due to complementation of two mutant p53, cancer cells need to delete the second p53 allele rather than mutate it...

..Therapy will control cancer if it can selectively suppress proliferating cancer cells and will improve survival as long as acquired resistance can be exploited...

..We infer that independence from mitogen-mediated signaling confers insensitivity to HER1 inhibitors in a large subset of cancer cell lines...

..We conclude that cellular senescence is characterized by futile hyper-mitogenic drive associated with mTOR-dependent mitotic incompetence...

..If a cell stays in mitosis too long, (e.g. mitotic arrest caused by Taxol or nocodazole), then p53 accumulates. This explains how p53 can measure mitotic time and perhaps represents the most fundamental function of p53...

..Also, I discuss that mitotic depletion of short-lived proteins collaborates with mitotic phosphorylation of p53, Bcl-2 and BclxL. Finally this article clarifies notions of apoptosis-prone and -reluctant cells and mitotic catastrophe...

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..We conclude that HDIs have differential effects on non-histone deacetylases and that rapid acetylation of tubulin caused by TSA is a marker of nontranscriptional effects of TSA...

..The concept of hypermitogenic arrest defines cell senescence as a functionally active, stable and conditionally reversible state...

..When depicted in multidimensional axis, this universal model may also include invasiveness, senescence, metastatic and angiogenic responses and even such integral characteristics as malignant transformation...

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..Following pretreatment with low doses of kinase inhibitors, the chemotherapy that predominantly induces apoptosis in cycling cells (cyclotherapy) will kill cancer cells while sparing normal cells...

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..In growth-limiting conditions, cells that express telomerase and inactivate tumor suppressors have a selective advantage due to resistance to growth arrest. Accidentally such cells become immortal...

..By abolishing several dose-limiting side effects of chemotherapy, this strategy provides a means to treat selectively most deranged, aggressive and resistant cancers...

..And finally, these strategies will benefit from molecular diagnostics and can be used for chemoprevention...

..Although Bcr-Abl renders cells hyper-sensitive, an excess of Bcr-Abl results in resistance (due to the remaining activity). We discuss therapeutic approaches to overcome bi-phasic resistance to mechanisms-based agents...

..The pharmacological industry could develop low cost, effective therapeutic modalities, by "re-using" already marketed and late-stage products in cancer-selective therapeutic kits...

..In theory, consecutive use of these drug combinations may control cancer...

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..These in vitro findings suggest a mechanism for the cytostatic activity of PTX in CASMC for the inhibition of restenosis...

..Finally, I discuss that extended life span will reveal new causes for aging (e.g., ROS, 'wear and tear', Hayflick limit, stem cell exhaustion) that play a limited role now, when quasi-programmed senescence kills us first...

..Using rational drug combinations, such selective agents can assist natural agents to eradicate cancer cells selectively...

..Cooperation between the HIF-1 and AP-1 pathways allows fine regulation of gene expression during hypoxia...

..Biologically active serum concentrations were achieved, and 1 patient obtained a partial response. The recommended Phase II dose is 17.8 mg/m(2) administered on day 1 and 5 of a 21-day cycle...

..This rational sequence of agents that induces p53-dependent and abrogates p53-independent arrest represents a cancer-selective strategy for treatment of p53-deficient tumors...

..This article reviews the molecular and cellular effects of flavopiridol as well as mechanisms of therapeutic and side effects, suggesting its novel clinical applications as a single agent and in drug combinations...

..Transient inhibition of p53- stimulated transcription by numerous stimuli including nucleotide depletion, hypoxia, UV light may be an prevalent mechanism of activation of wt p53 and its downstream pathways...

..We hypothesize that sequestration of RPA by p53 at the sites of recombination is one means by which p53 can inhibit HR processes. Our data support and extend the previously formulated 'dual model' of p53's role as guardian of the genome...

..But why aren't all cytotoxins carcinogenic?..

..Finally, we discuss how loss of the restriction point in cancer leads to loss of checkpoint control and to insensitivity to antimitogens including some mechanism-based anticancer therapeutics...

..Second, only successful antiangiogenic therapy, which is capable of controlling cancer, will select for resistance and progression. After all, in order to occur, therapy-induced tumor progression must be preceded by tumor regression...

..This approach may be most beneficial to patients who do not respond to monotherapy with kinase inhibitors. Development of molecular diagnostics will further diversify these strategies...

..This study validates the concept of pseudo-null p53, as a mechanism of p53 inactivation, and demonstrates that pseudo-null p53 can be rescued pharmacologically...

..These observations suggest both independent and overlapping roles for Raf-1 and Bcl-2 oncogenes in the resistance to growth inhibition by doxorubicin...