sirolimus and navitoclax

To summarize the state of chronic, treated HIV infection and its contribution to accelerated aging, and to evaluate recent research relevant to the study and treatment of aging and senescence.. Chronic treated HIV-1 infection is associated with significant risk of end-organ impairment, non-AIDS-associated malignancies, and accelerated physiologic aging. Coupled with the chronologic aging of the HIV-1-positive population, the development of therapies that target these processes is of great clinical importance. Age-related diseases are partly the result of cellular senescence. Both immune and nonimmune cell subsets are thought to mediate this senescent phenotype, a state of stable cell cycle arrest characterized by sustained release of pro-inflammatory mediators. Recent research in the field of aging has identified a number of 'senotherapeutics' to combat aging-related diseases, pharmacologic agents that act either by selectively promoting the death of senescent cells ('senolytics') or modifying senescent phenotype ('senomorphics').. Senescence is a hallmark of aging-related diseases that is characterized by stable cell cycle arrest and chronic inflammation. Chronic HIV-1 infection predisposes patients to aging-related illnesses and is similarly marked by a senescence-like phenotype. A better understanding of the role of HIV-1 in aging will inform the development of therapeutics aimed at eliminating senescent cells that drive accelerated physiologic aging.

Topics: Aging; Aniline Compounds; Antibiotics, Antineoplastic; Antineoplastic Agents; Antiretroviral Therapy, Highly Active; Bridged Bicyclo Compounds, Heterocyclic; Cardiovascular Diseases; CD4-CD8 Ratio; Cell Cycle Checkpoints; Cellular Senescence; Histone Deacetylase Inhibitors; HIV Infections; HIV-1; Humans; Inflammation; Janus Kinases; Nitriles; Panobinostat; Pyrazoles; Pyrimidines; Sirolimus; Sulfonamides; T-Lymphocyte Subsets

mTOR is a central regulator of cellular growth and metabolism. Using metabolic profiling and numerous small-molecule probes, we investigated whether mTOR affects immediate control over cellular metabolism by posttranslational mechanisms. Inhibiting the FKBP12/rapamycin-sensitive subset of mTOR functions in leukemic cells enhanced aerobic glycolysis and decreased uncoupled mitochondrial respiration within 25 min. mTOR is in a complex with the mitochondrial outer-membrane protein Bcl-xl and VDAC1. Bcl-xl, but not VDAC1, is a kinase substrate for mTOR in vitro, and mTOR regulates the association of Bcl-xl with mTOR. Inhibition of mTOR not only enhances aerobic glycolysis, but also induces a state of increased dependence on aerobic glycolysis in leukemic cells, as shown by the synergy between the glycolytic inhibitor 2-deoxyglucose and rapamycin in decreasing cell viability.

Topics: Aniline Compounds; bcl-X Protein; Glycolysis; Humans; In Vitro Techniques; Intracellular Signaling Peptides and Proteins; Jurkat Cells; Metabolome; Mitochondria; Oxygen Consumption; Protein Serine-Threonine Kinases; Sirolimus; Sulfonamides; TOR Serine-Threonine Kinases; Voltage-Dependent Anion Channel 1

ABT-263 is a potent, orally bioavailable inhibitor of the antiapoptotic Bcl-2 family members Bcl-2, Bcl-x(L), and Bcl-w, which is currently in phase I clinical trials. Previous work has shown that this compound has low nanomolar cell-killing activity in a variety of lymphoma and leukemia cell lines, many of which overexpress Bcl-2 through a variety of mechanisms. Rapamycin is a macrolide antibiotic that inhibits the mammalian target of rapamycin complex, leading to cell cycle arrest and inhibition of protein translation. Rapamycin (and its analogues) has shown activity in a variety of tumor cell lines primarily through induction of cell cycle arrest. Activity has also been shown clinically in mantle cell lymphoma and advanced renal cell carcinoma. Here, we show that treatment of the follicular lymphoma lines DoHH-2 and SuDHL-4 with 100 nmol/L rapamycin induces substantial G(0)-G(1) arrest. Addition of as little as 39 nmol/L ABT-263 to the rapamycin regimen induced a 3-fold increase in sub-G(0) cells. Combination of these agents also led to a significant increase in Annexin V staining over ABT-263 alone. In xenograft models of these tumors, rapamycin induced a largely cytostatic response in the DoHH-2 and SuDHL-4 models. Coadministration with ABT-263 induced significant tumor regression, with DoHH-2 and SuDHL-4 tumors showing 100% overall response rates. Apoptosis in these tumors was significantly enhanced by combination therapy as measured by staining with an antibody specific for cleaved caspase-3. These data suggest that combination of ABT-263 and rapamycin or its analogues represents a promising therapeutic strategy for the treatment of lymphoma.

Topics: Aniline Compounds; Animals; Antineoplastic Agents; Cell Cycle; Cell Death; Cell Line, Tumor; Drug Synergism; Humans; Immunohistochemistry; Lymphoma, Large B-Cell, Diffuse; Mice; Mice, SCID; Remission Induction; Sirolimus; Sulfonamides; Xenograft Model Antitumor Assays