A novel sulindac derivative inhibits lung adenocarcinoma cell growth through suppression of Akt/mTOR signaling and induction of autophagy
Menée sur des lignées cellulaires humaines de cancer du poumon, cette étude montre qu'un composé dérivé du sulfure de sulindac, le N,N-diméthyléthylamine, peut inhiber la croissance cellulaire d'un adénocarcinome du poumon via la suppression de la voie de signalisation Akt/mTOR et l'activation du processus d'autophagie
Nonsteroidal anti-inflammatory drugs (NSAIDs) such as sulindac sulfide (SS) have shown promising antineoplastic activity in multiple tumor types, but toxicities resulting from cyclooxygenase (COX) inhibition limit their use in cancer therapy. We recently described a N,N-dimethylethyl amine derivative of SS, sulindac sulfide amide (SSA), that does not inhibit COX-1 or -2, yet displays potent tumor cell growth inhibitory activity. Here, we studied the basis for the growth inhibitory effects of SSA on human lung adenocarcinoma cell lines. SSA potently inhibited the growth of lung tumor cells with IC50 values of 2-5 µM compared with 44-52 µM for SS. SSA also suppressed DNA synthesis and caused a G0/G1 cell cycle arrest. SSA-induced cell death was associated with characteristics of autophagy, but significant caspase activation or PARP cleavage were not observed after treatment at its IC50 value. siRNA knockdown of Atg7 attenuated SSA-induced autophagy and cell death, while pan-caspase inhibitor ZVAD was not able to rescue viability. SSA treatment also inhibited Akt/mTOR signaling and the expression of downstream proteins that are regulated by this pathway. Overexpression of a constitutively active form of Akt was able to reduce autophagy markers and confer resistance to SSA-induced cell death. Our findings provide evidence that SSA inhibits lung tumor cell growth by a mechanism involving autophagy induction through the suppression of Akt/mTOR signaling. This unique mechanism of action along with its increased potency and lack of cyclooxygenase inhibition support the development of SSA or related analogs for the prevention and/or treatment of lung cancer.
http://mct.aacrjournals.org/content/early/2013/02/26/1535-7163.MCT-12-0785.abstract