A key clinical problem in oncology is the treatment of apoptosis-resistant tumors. Tumor cells deficient in both of the proapoptotic proteins Bax and Bak are protected against most chemotherapeutic drug-induced apoptosis. We report here that a natural compound, oblongifolin C (OC), effectively eliminates Bax/Bak-deficient murine embryonic fibroblasts and colon carcinoma HCT116 cells. OC not only triggers DNA double-strand breaks and DNA damage response, but also inhibits repair of DNA damage. In addition, OC induces ER stress through upregulation of the transcription factor CHOP and activation of JNK kinases. Upon treatment with OC, cells undergo Bax/Bak-independent, caspase-mediated apoptosis. Taken together, our data establish a rationale for the broad use of OC to treat apoptosis deficient tumors. (C) 2015 Elsevier Inc. All rights reserved.