Synergistic Effects of Retinoic Acid and 8-Chloro-Adenosine 3′,5′-Cyclic Monophosphate on the Regulation of Retinoic Acid Receptor β and Apoptosis: Involvement of Mitochondria

• Published in: Clinical cancer research 1999-07, Vol.5 (7), p.1892-1904
• Main Authors: SRIVASTAVA, R. K, SRIVASTAVA, A. R, CHO-CHUNG, Y. S, LONGO, D. L
• Format: Article
• Language: English
• Subjects: 8-Bromo Cyclic Adenosine Monophosphate - analogs & derivatives; 8-Bromo Cyclic Adenosine Monophosphate - pharmacology; Antineoplastic agents; Antineoplastic Agents - pharmacology; Apoptosis; Biological and medical sciences; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cell Survival - drug effects; Chemotherapy; Cytochrome c Group - metabolism; DNA-Activated Protein Kinase; DNA-Binding Proteins; Drug Synergism; Gene Expression Regulation, Neoplastic - drug effects; Hormones - metabolism; Humans; Medical sciences; Mitochondria - drug effects; Nuclear Proteins; Pharmacology. Drug treatments; Poly Adenosine Diphosphate Ribose - metabolism; Protein-Serine-Threonine Kinases - metabolism; Receptors, Retinoic Acid - biosynthesis; Receptors, Retinoic Acid - drug effects; Receptors, Retinoic Acid - metabolism; Tretinoin - pharmacology; Tumor Cells, Cultured
• ISSN: 1078-0432; 1557-3265

In advanced or recurrent malignant diseases, retinoic acid (RA) is not effective, even at doses that are toxic to the host. In late stages of breast cancer, patients do not respond to RA because the expression of RA receptor β (RARβ) is lost. In the present study, the intracellular mechanism(s) of synergistic effects of RA and a site-selective cyclic AMP (cAMP) analogue, 8-chloro-adenosine 3′,5′-cyclic monophosphate (8-Cl-cAMP), on growth inhibition and apoptosis in breast cancer cells was examined. Our data demonstrated that hormone-dependent MCF-7 cells, but not hormone-independent MDA-MB-231 cells, are sensitive to RA-induced growth inhibition and apoptosis. Introduction of the RARβ gene into MDA-MB-231 cells resulted in a gain of RA sensitivity. 8-Cl-cAMP acted synergistically with all- trans -RA in inducing and activating RARβ gene expression that correlates with the reduction in mitochondrial membrane potential, redistribution of cytochrome c , activation of caspases, cleavage of poly(ADP-ribose) polymerase and DNA-dependent protein kinase (catalytic subunit), and induction of apoptosis. Mutations in the cAMP response element-related motif within the RARβ promoter resulted in loss of synergy in RARβ transcription. In addition, inhibition of RARβ expression by an antisense construct also blocked the antitumor effects of RA + 8-Cl-cAMP. Thus, RARβ can mediate RA and/or cAMP action in breast cancer cells by promoting apoptosis. Therefore, loss of RARβ expression may contribute to the tumorigenicity of human mammary epithelial cells. These findings suggest that RA and 8-Cl-cAMP act in a synergistic fashion and may have potential for combination biotherapy for the treatment of malignant diseases.