Cisplatin or carboplatin‐based chemotherapy is the standard of care for small cell lung cancer patients (SCLC). The challenge with SCLC treatment is that such chemotherapy shows excellent response initially; however, the tumor relapses within a year and is resistant to chemotherapy or radiation. Furthermore, a subset of SCLC is resistant to cisplatin (called platinum‐resistant SCLC) or displays platinum refractory phenotype. There is only one FDA‐approved drug for relapsed SCLC, which is camptothecin (irinotecan). It has been shown to display an objective response rate of about 3%. Therefore, agents which can increase the response rate of camptothecin should be of considerable benefit to SCLC patients. We tested the combinatorial effects of the nutritional compound capsaicin with camptothecin in human SCLC. Caspase‐3 activity assays reveal that the combination of camptothecin and capsaicin displayed greater apoptotic activity than any of the compounds used alone. Chicken chorioallantoic membrane assays confirmed the combinatorial effects of capsaicin and camptothecin. Statistical analysis using the Chou‐Talalay isobologram showed that capsaicin displayed synergistic apoptotic activity with camptothecin. The clinical development of capsaicin as a viable anti‐cancer drug is limited due to its adverse side effect profile. Our laboratory has performed structure‐activity relationship (SAR) studies to identify non‐pungent capsaicin analogs. One of those analogs, Arvanil, has shown synergistic apoptotic activity with SN‐38 (active drug component of irinotecan) in cisplatin‐resistant SCLC cells. Chou‐Talalay isobologram analysis showed that the magnitude of synergy between arvanil and SN‐38 was greater than capsaicin and SN‐38 in cisplatin‐resistant H69 human SCLC cells. The results of our studies will pave the way for novel second‐line treatment regimens for human SCLC.Support or Funding InformationFunding for our study was supported by an NIH R15‐AREA Grant (2R15CA161491‐02) and a WVU‐MU Health Partnership Grant. This work was supported in part by the West Virginia IDeA Network of Biomedical Research Excellence (WV‐INBRE) grant GM103434 (PI: Dr. G. Rankin).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.