Effect of rapamycin, an mTOR inhibitor, on radiation sensitivity of lung cancer cells having different p53 gene status

Abstract

Abstract. Activation to a large extent of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway and mutations in the p53 gene are involved in lung cancer therapeutic resistance. The mammalian target of rapamycin (mTOR) acts as a downstream effector for Akt. Activation of the Akt/mTOR signal is a contributing factor to decreased radiation sensitivity. The purpose of this study was to examine whether the effect of rapamycin on radiation sensitivity is affected by cellular p53 gene status. Cellular radiation sensitivity was evaluated by using two human non-small cell lung cancer (NSCLC) cell lines with the same genetic background except for their p53 gene status (H1299/wtp53 and H1299/mp53). The cells were treated with rapamycin and/or radiation. Cell viability, cell proliferation, apoptosis, cell cycle and Akt/mTOR signaling activity were explored. Rapamycin synergistically enhanced the cytotoxicity of radiation, promoting the induction of apoptosis. Moreover, the combined treatment augmented the cytostatic effects of radiation regardless of cellular p53 gene status. Rapamycin in combination with radiation increased G 1 arrest and suppressed progression to S phase in both cell lines. Furthermore, the combined treatment conduced to a prominent p53-independent down-regulation of the mTOR signal and pro-survival molecule, cyclin D1. Rapamycin can enhance the effect of radiation through the repression of prosurvival signals and the reduction in the apoptotic threshold. Taken together, inhibition of the mTOR signal may be a promising strategy for radiosensitization with no relevance to p53 gene status from the aspects of cell lethality and cell growth depression.

Rapamycin synergizes with low-dose oxaliplatin in the HCT116 colon cancer cell line by inducing enhanced apoptosis

“…At the concentration of 10 nM RAPA was found not to induce significant apoptosis, consistent with its cytostatic effect on cancer cell lines, as reported recently (17)(18)(19). This result indicated the significance of using a combination of low-dose RAPA with L-OHP in the clinic, in that the combined therapy led to less toxicity and better tolerability.…”

Crosstalk between autophagy and intracellular radiation response (Review)

“…The blockade of the mTORC1 can activate the ULK1 complex and promote the interaction with the PtdIns3K complex which is necessary for the formation of new autophagosomes (47). Several studies have reported on the positive effects of mTOR inhibitor on sensitizing cancers to radiation therapy and chemotherapy in lung cancer, pancreatic carcinoma cells and esophageal carcinoma cells (48)(49)(50)(51).…”

Overexpression of the mammalian target of rapamycin (mTOR) and angioinvasion are poor prognostic factors in early stage NSCLC: A verification study

“…Increased mTOR phosphorylation is frequently observed alongside activated Akt in NSCLC and dysregulation of mTOR contributes to lung cancer progression [18,19]. Several studies have shown that mTOR inhibition enhances the cytotoxic effects of chemotherapeutic agents and radiation in cancer [20][21][22][23]. These observations led to the evaluation of the antiproliferative effects of rapamycin and its derivatives (rapalogs), including the cell cycle inhibitor (CCI)-779 (temsirolimus), RAD001 (everolimus), and AP23573 (deforolimus), in malignant neoplasms [24].…”