title: Connexin-dependent gap junction enhancement is involved in the synergistic effect of sorafenib and all-trans retinoic acid on HCC growth inhibition.
abstract: Increasing gap junction activity in tumor cells provides a target by which to enhance antineoplastic therapies. Previously, several naturally occurring agents, including all-trans retinoic acid (ATRA) have been demonstrated to increase gap junctional intercellular communication (GJIC) in a number of types of cancer cells. In the present study, we investigated in vitro whether ATRA modulates the response of human hepatocellular carcinoma (HCC) cells to sorafenib, the only proven oral drug for advanced HCC, and the underlying mechanisms. HepG2 and SMMC-7721 cells were treated with sorafenib and/or ATRA, and cell proliferation and apoptosis were analyzed; the role of GJIC was also explored. We found that ATRA, at non-toxic concentrations, enhanced sorafenib-induced growth inhibition in both HCC cell lines, and this effect was abolished by two GJIC inhibitors, 18-α-GA and oleamide. Whereas lower concentrations of sorafenib (5 µM) or ATRA (0.1 or 10 µM) alone modestly induced GJIC activity, the combination of sorafenib plus ATRA resulted in a strong enhancement of GJIC. However, the action paradigm differed in the HepG2 and SMMC-7721 cells, with the dominant effect of GJIC dependent on the cell-specific connexin increase in protein amounts and relocalization. RT-PCR assay further revealed a transcriptional modification of the key structural connexin in the two cell lines. Thus, a connexin-dependent gap junction enhancement may play a central role in ATRA plus sorafenib synergy in inhibiting HCC cell growth. Since both agents are available for human use, the combination treatment represents a future profitable strategy for the treatment of advanced HCC.
authors: Department of Medical Oncology, The First Affiliated Hospital of Bengbu Medical College, Bengbu 233004, P.R. China.
authors: Yan
authors: Y
authors: Yang
authors: Department of Medical Oncology, PLA Cancer Center, Nanjing Bayi Hospital, Nanjing 210002, P.R. China.
authors: Shu-Kui
authors: SK
authors: Qin
authors: Department of Medical Oncology, The First Affiliated Hospital of Bengbu Medical College, Bengbu 233004, P.R. China.
authors: Qiong
authors: Q
authors: Wu
authors: Department of Medical Oncology, The First Affiliated Hospital of Bengbu Medical College, Bengbu 233004, P.R. China.
authors: Zi-Shu
authors: ZS
authors: Wang
authors: Department of Medical Oncology, The First Affiliated Hospital of Bengbu Medical College, Bengbu 233004, P.R. China.
authors: Rong-Sheng
authors: RS
authors: Zheng
authors: Department of Pharmacy, Bengbu Medical College, Bengbu 233000, P.R. China.
authors: Xu-Hui
authors: XH
authors: Tong
authors: Department of Pharmacy, Bengbu Medical College, Bengbu 233000, P.R. China.
authors: Hao
authors: H
authors: Liu
authors: Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, P.R. China.
authors: Liang
authors: L
authors: Tao
authors: Department of Intensive Care, The First Affiliated Hospital of Bengbu Medical College, Bengbu 233004, P.R. China.
authors: Xian-Di
authors: XD
authors: He
mesh_terms: D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy*; D002450:Cell Communication / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D017630:Connexins / Q000096:biosynthesis* / Q000378:metabolism; D004357:Drug Synergism; D017629:Gap Junctions / Q000473:pathology*; D006034:Glycyrrhetinic Acid / Q000494:pharmacology; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy*; D009536:Niacinamide / Q000031:analogs & derivatives / Q000494:pharmacology; D009829:Oleic Acids / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D000077157:Sorafenib; D014212:Tretinoin / Q000494:pharmacology
chemical_list: D000893:Anti-Inflammatory Agents; D000970:Antineoplastic Agents; D017630:Connexins; D009829:Oleic Acids; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D009536:Niacinamide; D014212:Tretinoin; C029407:oleylamide; D000077157:Sorafenib; D006034:Glycyrrhetinic Acid