PIAs also boost the apoptosis induced by other agents such as tumor necrosis factor related ligand , all trans retinoic acid and motexafin gadolinium . Triciribine . API , also referred to as triciribine phosphate, was identified as an Akt inhibitor immediately after screening the National Cancer Institute ?s structural diversity set. Triciribine inhibits Akt phosporylation at each websites and inhibits EGF induced phosphorylation of all three isoforms of Akt in vitro. In vivo, remedy with low doses of triciribine stimulated apoptosis in xenografts with constitutively activated Akt or PTEN mutations, but not in tumors with low Akt activity . Triciribine has not been preclinically combined with standard chemotherapies or radiation. . mTOR inhibitors: rapamycin and its analogues The PIK Akt mTOR pathway inhibitors which can be most clinically created, target a far more distal pathway component, mTOR. Rapamycin, the prototypic mTOR inhibitor, was found in as a potent anti fungicide, and is developed naturally by Streptomyces hygroscopicus . The potential of rapamycin to inhibit the proliferation of cancer cell lines was shown more than years ago .
Extra not too long ago, rapamycin analogues similar to CCI and RAD have been explicitly made for improvement as anticancer drugs. These inhibitors of mTOR bind to the FK binding protein, FKBP , which then binds and inhibits mTOR. Inhibition of mTOR decreases phosphorylation of two downstream targets, E BP and SK, resulting in inhibition of protein synthesis. Rapamycin and its analogues peptide synthesis have already been studied in mixture with typical chemotherapies. For instance, remedy of orthotopic neuroblastoma bearing mice with rapamycin and vinblastine resulted in inhibition of tumor growth and angiogenesis, with an increase in survival compared to either drug alone . Related results were observed in hepatocellular carcinoma . In vitro, synergy has been observed with rapamycin and paclitaxel, carboplatin, or vinorelbine. In lymphoma models, RAD demonstrates in vitro synergy with rituximab, doxorubicin, and vincristine , predominantly by way of induction of cell cycle arrest.
Combinations of RAD and anti estrogen agents tamoxifen and letrozole also demonstrated enhanced levels of apoptosis than with either drug alone . Interestingly, RAD sensitizes tumor cells to cisplatin induced Daidzin apoptosis in a p dependent manner by way of inhibition ofmTORfunction, resulting in lowered p translation . CCI , one other rapamycin analogue, has been effectively combined with cisplatin, gemcitabine, and camptothecin in vitro and in vivo . Rapamycin and RAD are also potent radiosensitizers by means of mTOR dependent enhancement of radiationinduced autophagy . In a recent study, RAD sensitized PTEN wild variety and PTEN null cancer cells to ionizing radiation, but induced much more cytotoxicity in PTEN null cells .