3α,23-Isopropylidenedioxyolean-12-en-27-oic Acid, a Triterpene Isolated from Aceriphyllum rossii, Induces Apoptosis in Human Cervical Cancer HeLa Cells through Mitochondrial Dysfunction and Endoplasmic Reticulum Stress

• Published in: Biological & Pharmaceutical Bulletin Vol. 33; no. 9; pp. 1620 - 1626
• Main Authors: Won, So-Jung, Ki, Yo Sook, Chung, Kyung-Sook, Choi, Jung-Hye, Bae, Ki Hwan, Lee, Kyung-Tae
• Format: Journal Article
• Language: English
• Published: Japan The Pharmaceutical Society of Japan 2010; Pharmaceutical Society of Japan
• Subjects: 3α,23-isopropylidenedioxyolean-12-en-27-oic acid; apoptosis; Apoptosis - drug effects; Apoptosis - physiology; caspase; Dose-Response Relationship, Drug; Endoplasmic Reticulum - drug effects; Endoplasmic Reticulum - metabolism; endoplasmic reticulum stress; HeLa cell; HeLa Cells; Humans; Mitochondria - drug effects; Mitochondria - physiology; mitochondrial dysfunction; Oleanolic Acid - isolation & purification; Oleanolic Acid - pharmacology; Oxidative Stress - drug effects; Oxidative Stress - physiology; Plant Extracts - isolation & purification; Plant Extracts - pharmacology; Saxifragaceae; Triterpenes - isolation & purification; Triterpenes - pharmacology
• ISSN: 0918-6158; 1347-5215
• DOI: 10.1248/bpb.33.1620

In the present study, we investigated the effect of 3α,23-isopropylidenedioxyolean-12-en-27-oic acid (IPA), an active compound isolated from Aceriphyllum rossii, on the apoptotic activity and the molecular mechanism of the action in human cervical cancer HeLa cells. Treatment with IPA significantly increased externalization of phosphatidylserine residues and apoptotic DNA fragmentation as shown by Annexin V staining and 4′,6-diamidino-2-phenylindole-dihydrochloride (DAPI) staining, respectively. In addition, IPA induced the activations of caspase-8, -9, -3, and cleavage of poly(ADP ribose) polymerase (PARP-1) in HeLa cells. Pretreatment with a specific caspase-8, -9, or -3 inhibitor neutralized the pro-apoptotic activity of IPA in HeLa cells. Furthermore, IPA was found to induce the loss of mitochondrial membrane potential, the release of cytochrome c to the cytosol, and the increased ratio of mitochondrial Bax/Bcl-2. Moreover, we demonstrated that IPA triggered endoplasmic reticulum (ER) stress, as shown by changes in cytosol-calcium level, activation of μ-calpain and caspase-12, and up-regulation of glucose-regulated protein 78 (GRP78) and growth arrest DNA damage-inducible gene 153 (GADD153). IPA-induced apoptosis was substantially reduced in the presence of an intracellular calcium chelator BAPTA/AM. Taken together, these results suggest that both mitochondrial dysfunction and ER stress contribute to IPA-induced apoptosis of human cervical cancer HeLa cells.