Mammalian target of rapamycin inhibitor RAD001 sensitizes endometrial cancer cells to paclitaxel-induced apoptosis via the induction of autophagy

Abstract

The aim of the present study was to investigate the effects of the mammalian target of rapamycin (mTOR) inhibitor, RAD001, on the growth of human endometrial cancer cells. The effects of RAD001 on human endometrial cancer Ishikawa and HEC-1A cell proliferation were determined by MTT assay. Green fluorescent protein microtubule-associated protein 1 light chain 3α (GFP-LC3) protein aggregates were observed under a confocal microscope, and Ishikawa and HEC-1A cell apoptosis was detected using flow cytometry. The expression levels of LC3-I, LC3-II and mTOR proteins were detected by western blot analysis. The results showed that RAD001 effectively inhibited human endometrial cancer Ishikawa and HEC-1A cell proliferation via downregulation of AKT/mTOR phosphorylation. Moreover, RAD001 induced autophagic cell death and a higher sensitivity to paclitaxel-induced apoptosis. These results indicate that RAD001 could have therapeutic potential in human endometrial cancer with hyperactivated AKT/mTOR signaling.

Hyperbaric oxygen treatment sensitizes gastric cancer cells to melatonin‐induced apoptosis through multiple pathways

“…Some evidences suggest that autophagy plays key roles in cancer treatment and is classified as an antitumor mechanism by promoting cancer cells apoptosis death. 37,38 LC3, a microtubule-associated protein, is associated with the autophagosomes formation and is recognized as a marker of autophagy. LC3 expression level was dramaticlly upregulated when gastric cancer cells were processed using HBO and MLT ( Figure 6).…”

Selective Inhibition of Kras Signaling by Combination of Low Dose Rapamycin and Paclitaxel in Vivo

“…Так, применение комбинации RAP и PAC ингибировало рост клеток линий рака молочной железы MCF-7 и MDAMB-468, при этом клеточные линии, которые были изначально резистентны к ингибирующему действию RAP, оказа-лись также не чувствительны к совместному действию RAP с химиотерапевтическими препаратами [5]. Ин-гибиторы mTOR (RAP и RAD001) тормозили проли-ферацию клеток рака эндометрия Ishikawa, ECC-1 и HEC-1A человека и повышали их чувствительность к апоптозу, индуцированному PAC [19]. Использование комбинации PAC и ингибиторов сигнального каскада PI3K/AKT (RAP и BEZ235) более эффективно тормо-зило рост клеток рака толстой кишки HCT-116 и HT-29, чем каждый из препаратов в отдельности [20].…”

Therapeutic Implications of Autophagy Inducers in Immunological Disorders, Infection, and Cancer

“…Everolimus was reported to suppress proliferation and enhance the anti-proliferative effect of paclitaxel when combined for the treatment of endometrial cancer cells. Co-treatment with the autophagy inhibitor chloroquine or transfection with shRNA targeting Atg5 reduced everolimus-mediated cell death, suggesting that everolimus induces autophagic cell death in endometrial cancer cells [ 98 ]. In another study, rapamycin was shown to sensitize A549 lung cancer cells to radiation therapy by inducing autophagy and delaying DNA damage repair [ 98 ].…”

“…Co-treatment with the autophagy inhibitor chloroquine or transfection with shRNA targeting Atg5 reduced everolimus-mediated cell death, suggesting that everolimus induces autophagic cell death in endometrial cancer cells [ 98 ]. In another study, rapamycin was shown to sensitize A549 lung cancer cells to radiation therapy by inducing autophagy and delaying DNA damage repair [ 98 ]. Rapamycin activated autophagy, but not apoptosis in malignant glioma cells.…”