2. Academic Validation
  3. Potential synthetic lethality for breast cancer: A selective sirtuin 2 inhibitor combined with a multiple kinase inhibitor sorafenib

Potential synthetic lethality for breast cancer: A selective sirtuin 2 inhibitor combined with a multiple kinase inhibitor sorafenib

  • Pharmacol Res. 2022 Mar;177:106050. doi: 10.1016/j.phrs.2021.106050.
Hua-Li Wang 1,  Xue Ma 2,  Xin-Yuan Guan 3,  Chen Song 4,  Guo-Bo Li 5,  Ya-Mei Yu 6,  Ling-Ling Yang 7
Affiliations

Affiliations

  • 1 Department of Clinical Oncology, The University of Hong Kong-Shenzhen Hospital, Shenzhen 518053, PR China; State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center of Biotherapy, Chengdu 610041, PR China.
  • 2 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center of Biotherapy, Chengdu 610041, PR China.
  • 3 Department of Clinical Oncology, The University of Hong Kong-Shenzhen Hospital, Shenzhen 518053, PR China.
  • 4 College of Food and Bioengineering, Xihua University, Sichuan 610039, PR China.
  • 5 Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Sichuan 610041, PR China.
  • 6 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center of Biotherapy, Chengdu 610041, PR China. Electronic address: yamei_yu@scu.edu.cn.
  • 7 College of Food and Bioengineering, Xihua University, Sichuan 610039, PR China. Electronic address: yangll0808@sina.com.
PMID: 34973468 DOI: 10.1016/j.phrs.2021.106050
Abstract

Sorafenib is a clinically useful multiple kinase inhibitor for the treatment of kidney Cancer, liver Cancer and acute myelocytic leukemia, while it has shown weak efficacy in suppressing breast Cancer. Since sirtuin2 (SIRT2) is an important epigenetic regulator and associated with several Cancer types including breast Cancer, development and evaluation of new SIRT2 inhibitors to probe their therapeutic potentials is currently desirable. A highly selective SIRT2 Inhibitor named I was previously developed by us, which showed activity to inhibit non-small cell lung Cancer cell lines in vitro. We herein report expanded screening of I and its structurally similar inactive compound II against other Cancer cell lines, and found that I had a wide spectrum of Anticancer activity while II had no such effects. The I-sorafenib combination treatment exerted obvious synergistic reduction on cell viability of MCF-7 cells. We observed that the combination treatment could suppress cell proliferation, survival and migration, arrest cell cycle at G0/G1 phase, and induce Apoptosis in MCF-7 cells, when compared with the single treatment. In vivo studies revealed that the combination treatment showed stronger tumor growth inhibition (87%), comparing with I-(42.8%) or sorafenib-solely-treated groups (61.1%) in MCF-7 xenograft model. In conclusion, this work clearly revealed a potential synthetic lethality effect for I combined with sorafenib, and will probably offer a new strategy at least for breast Cancer treatment.

Keywords

Breast cancer; Combination therapy; SIRT2; Sorafenib; Synthetic lethality.

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