A novel sulindac derivative inhibits lung adenocarcinoma cell growth through suppression of Akt/mTOR signaling and induction of autophagy.

Abstract

Nonsteroidal anti-inflammatory drugs such as sulindac sulfide have shown promising antineoplastic activity in multiple tumor types, but toxicities resulting from COX inhibition limit their use in cancer therapy. We recently described a N,N-dimethylethyl amine derivative of sulindac sulfide, 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 to 5 μmol/L compared with 44 to 52 μmol/L for sulindac sulfide. 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 was not observed after treatment at its IC50 value. siRNA knockdown of Atg7 attenuated SSA-induced autophagy and cell death, whereas 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 COX inhibition, supports the development of SSA or related analogs for the prevention and/or treatment of lung cancer.

• Authors: Evrim Gurpinar, William E Grizzle, John J Shacka, Burton J Mader, Nan Li, Nicholas A Piazza, Suzanne Russo, Adam B Keeton, Gary A Piazza
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 12 Issue 5 Pg. 663-74 (May 2013) ISSN: 1538-8514 [Electronic] United States
• PMID: 23443799 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: ©2013 AACR

Chemical References

• Antineoplastic Agents
• sulindac sulfide amide
• Sulindac
• sulindac sulfide
• Proto-Oncogene Proteins c-akt
• Ribosomal Protein S6 Kinases, 70-kDa
• TOR Serine-Threonine Kinases

Topics

• Adenocarcinoma (metabolism)
• Adenocarcinoma of Lung
• Antineoplastic Agents (pharmacology)
• Autophagy (drug effects)
• Cell Cycle (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Humans
• Inhibitory Concentration 50
• Lung Neoplasms (metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• Ribosomal Protein S6 Kinases, 70-kDa (metabolism)
• Signal Transduction (drug effects)
• Sulindac (analogs & derivatives, pharmacology)
• TOR Serine-Threonine Kinases (metabolism)