Antihyperlipidemic drug rosuvastatin suppressed tumor progression and potentiated chemosensitivity by downregulating CCNA2 in lung adenocarcinoma

Abstract

Rosuvastatin (RSV) is widely used to treat hyperlipidemia and hypercholesterolemia and is recommended for the primary and secondary prevention of cardiovascular diseases (CVD). In this study, we aimed to explore its action and mechanism in lung adenocarcinoma (LUAD) therapy. Lewis and CMT64 cell-based murine subcutaneous LUAD models were employed to explore the effects of RSV monotherapy combined with cisplatin and gemcitabine. Human lung fibroblasts and human LUAD cell lines were used to assess the effects of RSV on normal and LUAD cells. Bioinformatics and RNA interference were used to observe the contribution of cyclin A2 (CCNA2) knockdown to RSV inhibition and to improve chemosensitivity in LUAD. RSV significantly suppressed grafted tumor growth in a murine subcutaneous LUAD model and exhibited synergistic anti-tumor activity with cisplatin and gemcitabine. In vitro and in vivo experiments demonstrated that RSV impaired the proliferation and migration of cancer cells while showing little inhibition of normal lung cells. RNA interference and CCK8 detection preliminarily indicated that RSV inhibited tumor growth and enhanced the chemosensitivity to cisplatin and gemcitabine by downregulating CCNA2. RSV suppressed LUAD progression and enhanced chemosensitivity to cisplatin and gemcitabine by downregulating CCNA2, which should be prior consideration for the treatment of LUAD, especially for patients co-diagnosed with hyperlipidemia and hypercholesterolemia.

Keywords:

• Rosuvastatin
• hyperlipemia
• LUAD
• cisplatin
• gemcitabine
• CCNA2

Acknowledgments

We are thankful to Guangzhou Medical University for providing facilities and technical support.

Ethical approval

Animal handling in all experiments were abided by the Care and Use of Laboratory Animals of the National Institutes of Health (NIH) guidelines. The tumor sizes and weights in mice were guaranteed not to exceed the recommendations of the University of Pennsylvania Institutional Animal Care and Use Committee guidelines. The scheme was approved by the Animal Care and Use Committee of Guangzhou University.

Authors contributions

Conceptualization: XD; Methodology: XD, CF, and SY; Investigation: XD, CF, and SY; Visualization: XD, CF, and SY; Funding acquisition: XD and SY; Project administration: XD; Supervision: XD and SY; Writing–original draft: XD and SY; Writing–review and editing: XD, CF, and SY.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Supplementary materials

Supplementary material Fig.S1. RSV treatment reduced CH content and effect of other statins exerting on LUAD cells growth. (A) CH content of A549 after RSV (100 μM) treatment for 48h. (B) qP CR detection of RSV (100 μM), LOV(100 μM), SIV(100 μM) effect on A549 cells after 48h treatment. (C) CCK8 detection of cell viability after RSV (100 μM), LOV (100 μM), SIV (100 μM) combined with gemcitabine (20 μM), and cisplatin (20 μM) for 48h. All results are presented as mean ± SD. Significance levels were defined as *P < 0.05, **P < 0.01, ***P < 0.001, P values were calculated by GraphPad Prism 9.0.

Data availability statement

All data are available in the main text or the supplementary materials.

Additional information

Funding

Natural Science Foundation of Guangdong Province [No. 2018A030313980].