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

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A Data Integration Workflow to Identify Drug Combinations Targeting Synthetic Lethal Interactions
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A Data Integration Workflow to Identify Drug Combinations Targeting Synthetic Lethal Interactions

Published on: May 27, 2021

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Hua-Li Wang1, Xue Ma2, Xin-Yuan Guan3

  • 1Department 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.

Pharmacological Research
|January 1, 2022
PubMed

Insights

A novel sirtuin2 (SIRT2) inhibitor, compound I, combined with sorafenib, demonstrates significant synergistic effects against breast cancer. This combination therapy shows broad anticancer activity and offers a promising new strategy for cancer treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Epigenetics

Background:

  • Sorafenib is a kinase inhibitor with limited efficacy in breast cancer.
  • Sirtuin2 (SIRT2) is an epigenetic regulator implicated in various cancers, including breast cancer.
  • Targeting SIRT2 presents a potential therapeutic strategy for cancers resistant to current treatments.

Purpose of the Study:

  • To evaluate the anticancer activity of a selective SIRT2 inhibitor, compound I, and its combination with sorafenib.
  • To investigate the synergistic effects of compound I and sorafenib in breast cancer cell lines and xenograft models.
  • To explore the underlying mechanisms of the combination therapy's efficacy.

Main Methods:

  • In vitro screening of compound I and its inactive analog II against diverse cancer cell lines.
  • Assessment of cell viability, proliferation, survival, migration, cell cycle, and apoptosis in MCF-7 cells treated with compound I and sorafenib.
  • In vivo efficacy studies using a MCF-7 xenograft mouse model to evaluate tumor growth inhibition.

Main Results:

  • Compound I exhibited broad-spectrum anticancer activity, while compound II showed no such effects.
  • The combination of compound I and sorafenib demonstrated synergistic reduction in MCF-7 cell viability.
  • Combination treatment suppressed proliferation, survival, and migration, induced G0/G1 cell cycle arrest and apoptosis, and significantly enhanced tumor growth inhibition in vivo.

Conclusions:

  • The combination of compound I and sorafenib exhibits a potential synthetic lethality effect, offering a promising therapeutic strategy for breast cancer.
  • Compound I demonstrates significant anticancer potential, particularly when used in combination with established therapies like sorafenib.
  • Further research into SIRT2 inhibition could lead to novel treatments for various cancer types.
Keywords:
Breast cancerCombination therapySIRT2SorafenibSynthetic lethality

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