The studies of rapamycin as immunosuppressive agent enabled us to understand its mechanism of action. It inhibits T-cell proliferation and proliferative responses induced by several cytokines, including interleukin 1 (IL-1), IL-2, IL-3, IL-4, IL-6, IGF, PDGF, and colony-stimulating factors (CSFs). Rapamycin inhibitors and rapalogs can target tumor growth both directly and indirectly. Direct impact of them on cancer cells depend on the concentration of the drug and certain cellular characteristics. The indirect way, is based on interaction with processes required for tumor angiogenesis. Effects in cancer cells Effects of rapamycin and rapalogs in cancer cells Rapamycin and rapalogs crosslink the immunophilin FK506 binding protein, tacrolimus or FKBP-12, through its methoxy group. The rapamycin-FKBP12 complex interferes with FRB domain of<unk> . Molecular interaction between FKBP12,<unk> , and rapamycin can last for about three days (72 hours). The inhibition of<unk>  blocks the binding of the accessory protein raptor (regulatory-associated protein of<unk>  to<unk> , but that is necessary for downstream phosphorylation of S6K1 and 4EBP1. As a consequence, S6K1 dephosphorylates, which reduces protein synthesis and decreases cell mortality and size. Rapamycin induces dephosphorylation of 4EBP1 as well, resulting in an increase in p27 and a decrease in cyclin D1 expression. That leads to late blockage of G1/S cell cycle. Rapamycin has shown to induce cancer cell death by stimulating autophagy or apoptosis, but the molecular mechanism of apoptosis in cancer cells has not yet been fully resolved. One suggestion of the relation between<unk>  inhibition and apoptosis might be through the downstream target S6K1, which can phosphorylate BAD, a pro-apoptotic molecule, on Ser136. That reaction breaks the binding of BAD to BCL-XL and BCL2, a mitochondrial death inhibitors, resulting in inactivation of BAD and decreased cell survival. Rapamycin has also shown to induce p53-independent apoptosis in certain types of cancer. Effects on tumor angiogenesis Effects of rapamycin and rapalogs on endothelial and tumor cells Tumor angiogenesis rely on interactions between endothelial vascular growth factors which can all activate the PI3K/AKT/mTOR in endothelial cells, pericytes, or cancer cells. Example of these growth factors are angiopoietin 1 (ANG1), ANG 2, basic fibroblast growth factor (bFGF), ephrin-B2, vascular endothelial growth factor (VEGF), and members of the tumor growth factor-β (TGFβ) superfamily. One of the major stimuli of angiogenesis is hypoxia, resulting in activation of hypoxia-inducible transcription factors (HIFs) and expression of ANG2, bFGF, PDGF, VEGF, and VEGFR. Inhibition of HIF1α translation by preventing PDGF/PDGFR and VEGF/VEGFR can result from<unk>  inhibition. A G0-G1 cell-cycle blockage can be the consequence of inactivation of<unk>  in hypoxia-activated pericytes and endothelial cells. There is some evidence that extended therapy with rapamycin may have effect on AKT and<unk> C2 as well. Effects on chemotherapy Pharmacologic down-regulation of <unk>  pathway during chemotherapy in a mouse model prevents activation of primordial follicles, preserves ovarian function, and maintains normal fertility using clinically available inhibitors INK and RAD. In that way, it helps to maintain fertility while undergoing chemotherapy treatments. These<unk> , when administrated as pretreatment or co-treatment with standard gonadotoxic chemotherapy, helps to maintain ovarian follicles in their primordial state. Effects on cognition<unk>  promotes the protein synthesis required for synaptic plasticity. Studies in cell cultures and hippocampal slices indicate that<unk>  inhibition reduces long-term potentiation.<unk>  activation can protect against certain neurodegeneration associated with certain disease conditions. On the other hand, promotion of autophagy by<unk>  inhibition may reduce cognitive decline associated with neurodegeneration. Moderate reduction of<unk>  activity by 25-30% has been shown to improve brain function, suggesting that the relation between<unk>  and cognition is optimized with intermediate doses (2.24 mg/kg/day in mice, human equivalent about 0.19 mg/kg/day), where very high or very low doses impair cognition. Reduction of the inflammatory cytokine Interleukin 1 beta (IL-1β) in mice by<unk>  inhibition (with rapamycin in doses of 20 mg/kg/day, human equivalent about 1.6 mg/kg/day) has been shown to enhance learning and memory. Although IL-1β is required for memory, IL-1β normally increases with age, impairing cognitive function.
MTOR inhibitors
Reuptake inhibitor
COX-2 inhibitor
GABA analogue
CDK inhibitor
RET inhibitor
C-Met inhibitor
Targeted covalent inhibitors