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J. Biol. Chem., Vol. 279, Issue 12, 11179-11187, March 19, 2004

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Evidence Supporting a Role for Calcium in Apoptosis Induction by the Synthetic Triterpenoid 2-Cyano-3,12-dioxooleana-1,9-dien-28-oic Acid (CDDO)^*

Numsen Hail, Jr., Marina Konopleva, Michael Sporn¶, Reuben Lotan, and Michael Andreeff||

From the Department of Thoracic/Head and Neck Medical Oncology, and the Department of Blood and Marrow Transplantation, Section of Molecular Hematology and Therapy, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030-4095 and the ^¶Department of Pharmacology, Dartmouth Medical School, Dartmouth College, Hanover, New Hampshire 03755-1404

The synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO) is a novel anticancer agent that induces apoptosis in tumor cells. The cytotoxic stress underpinning CDDO-induced apoptosis has not been established. This study compared and contrasted the effects of CDDO on COLO 16 human skin cancer cells and their respiration-deficient (⁰) clones to elucidate the stress signal responsible for initiating apoptosis. CDDO promoted apoptosis in COLO 16 cells in a dose- and time-dependent manner. The ⁰ clones appeared to be more sensitive to CDDO-induced apoptosis implying that the disruption of mitochondrial respiration was not directly associated with triggering cell death. After a 4-h exposure to CDDO, mitochondrial inner transmembrane potential-sensitive dyes revealed mitochondrial hyperpolarization in the COLO 16 cells and mitochondrial depolarization in the ⁰ clones. Electron microscopy illustrated that this exposure also promoted mitochondrial condensation, endoplasmic reticulum dilation, and chromatin condensation in the COLO 16 cells. Endoplasmic reticulum dilation and chromatin condensation were also observed in the ⁰ clones, but the mitochondria in these cells were markedly swollen implying that the disruption of intracellular Ca²⁺ homeostasis was associated with cell death. A Ca²⁺-sensitive dye confirmed that CDDO increased cytoplasmic free Ca²⁺ in the COLO 16 cells, their ⁰ clones, as well as in malignant breast and lung epithelial cells. A cell-permeant Ca²⁺ chelator reduced the CDDO-induced increase in cytoplasmic free Ca²⁺, and inhibited caspase activation, the development of apoptotic morphology, and DNA fragmentation in the COLO 16 cells, implying that Ca²⁺ played a pivotal role in signaling the initiation of apoptosis.

Received for publication, November 21, 2003 , and in revised form, January 6, 2004.

^* This work was supported in part by NCI/National Institutes of Health (NIH) Grant R25 CA57780 (to N. H.); Leukemia/Lymphoma Society Grant CF02-007 (to M. K.); NCI/NIH Grant PO1 CA68233 (to R. L.); NCI/NIH Grants PO1 CA55164, 1P50 CA100632-01, 2P30 CA16672, and RO1 CA89346; and a Goodwin Foundation Grant (to M. A.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence and request for reprints should be addressed: Dept. of Blood and Marrow Transplantation, Section of Molecular Hematology and Therapy, Box 448, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030-4095. Tel.: 713-792-7260; Fax: 713-794-4747; E-mail: mandreef{at}mdanderson.org.

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