Synergistic anti-tumor activity of miriplatin and radiation through PUMA-mediated apoptosis in hepatocellular carcinoma
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O R I G I N A L A R T I C L E¯ L I V E R , P A N C R E A S , A N D B I L I A R Y T R A C T
Synergistic anti-tumor activity of miriplatin and radiation through PUMA-mediated apoptosis in hepatocellular carcinoma Hironori Tanaka1 • Koichi Okamoto1 • Yasushi Sato1 • Takahiro Tanaka1 • Tetsu Tomonari1 • Fumika Nakamura1 • Yasuteru Fujino1 • Yasuhiro Mitsui1 • Hiroshi Miyamoto1 • Naoki Muguruma1 • Akinori Morita2 • Hitoshi Ikushima3 • Tetsuji Takayama1
Received: 7 July 2019 / Accepted: 29 June 2020 Ó Japanese Society of Gastroenterology 2020
Abstract Background The prognosis for patients with unresectable advanced hepatocellular carcinoma (HCC) is poor. Miriplatin is a hydrophobic platinum compound that has a long retention time in lesions after transarterial chemoembolization (TACE). We investigated anti-tumor activity of miriplatin combined with irradiation on HCC cells, and its underlying mechanism of apoptosis. We also analyzed the effectiveness of miriplatin-TACE and radiotherapy for locally advanced HCC. Methods Human HCC cell lines HepG2 and HuH-7 were treated with DPC (active form of miriplatin) and radiation, and synergy was evaluated using a combination index (CI). Apoptosis-related proteins and cell cycles were analyzed by western blotting and flowcytometry. We retrospectively analyzed treatment outcomes in 10 unresectable HCC patients with vascular/bile duct invasion treated with miriplatin-TACE and radiotherapy.
Results DPC or X-ray irradiation decreased cell viability dose-dependently. DPC plus irradiation decreased cell viability synergistically in both cell lines (CI \ 1, respectively). Cleaved PARP expression was induced much more strongly by DPC plus irradiation than by each treatment alone. Expression of p53 up-regulated modulator of apoptosis (PUMA) was significantly induced by the combination, and knockdown of PUMA with siRNA significantly decreased apoptosis in both cell lines. DPC plus irradiation caused sub-G1, G2/M, and S phase cell arrest in those cells. The combination of miriplatin-TACE and radiotherapy showed a high response rate for patients with locally advanced HCC despite small number of patients. Conclusions Miriplatin plus irradiation had synergistic anti-tumor activity on HCC cells through PUMA-mediated apoptosis and cell cycle arrest. This combination may possibly be effective in treating locally advanced HCC. Keywords Hepatocellular carcinoma Miriplatin Radiation Synergistic effect Apoptosis
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00535-020-01705-8) contains supplementary material, which is available to authorized users. & Tetsuji Takayama [email protected] 1
Department of Gastroenterology and Oncology, Tokushima University Graduate School of Biomedical Sciences, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan
2
Department of Biomedical Science and Technology, Tokushima University Graduate School of Biomedical Sciences, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan
3
Department of Therapeutic Radiolo
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