Propranolol enhanced the anti-tumor effect of sunitinib by inhibiting proliferation and inducing G0/G1/S phase arrest in malignant melanoma
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Xinwei Kuang1,2, Min Qi3, Cong Peng1,2, Chengfang Zhou4, Juan Su1,2, Weiqi Zeng1,2, Hong Liu1,2, Jianglin Zhang1,2, Mingliang Chen1,2, Minxue Shen1,2, Xiaoyun Xie5, Fangfang Li1,2, Shuang Zhao1,2, Qingling Li6, Zhongling Luo1,2, Junchen Chen1,2, Juan Tao7, Yijing He1,2 and Xiang Chen1,2
1Department of Dermatology, XiangYa Hospital, Central South University, Changsha, China
2Hunan Key Laboratory of Skin Cancer and Psoriasis, Changsha, China
3Department of Plastic and Cosmetic Surgery, XiangYa Hospital, Central South University, Changsha, China
4Department of Clinical Pharmacology, XiangYa Hospital, Central South University, Changsha, China
5Department of Rheumatology, XiangYa Hospital, Central South University, Changsha, China
6Department of Pathology, XiangYa Hospital, Central South University, Changsha, China
7Department of Dermatology, Affiliated Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
Xiang Chen, email: [email protected]
Yijing He, email: [email protected]
Keywords: malignant melanoma; sunitinib; propranolol; combination treatment; cell cycle
Received: August 24, 2017 Accepted: September 21, 2017 Published: November 25, 2017
Both sunitinib, a multi-target tyrosine kinase inhibitor (TKI) and propranolol, a non-selective β-blocker, have proven therapeutic effects on malignant melanoma (MM). This study reports a synergistic effect of propranolol and sunitinib upon A375, P8 MM cell lines and mice xenografts. Cell viability assays detected a significant decrease of sunitinib IC50 in combination with propranolol, which was confirmed by a colony formation assay. Western blot showed that propranolol and sunitinib combination significantly down-regulated phospho-Rb, phospho-ERK, Cyclin D1, and Cyclin E, but had no effect on Bax, Bcl-2, or cleaved PARP expression. The average tumor size of propranolol and low-dose sunitinib (Sun L) combination treated mice was reduced and similar to high-dose sunitinib treated A375 xenografts. The Ki67 index was significantly reduced in propranolol and Sun L combination treated group compared with single Sun L treated group. This synergistic effect between propranolol and sunitinib to inhibit MM proliferation was through suppressing ERK/Cyclin D1/Rb/Cyclin E pathways and inducing G0/G1/S phase arrest, rather than by inducing tumor cell apoptosis.
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