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Synergistic Anticancer Effects of Gemcitabine with Pitavastatin on Pancreatic Cancer Cell Line MIA PaCa-2 in vitro and in vivo

Authors Chen YH, Chen YC, Lin CC, Hsieh YP, Hsu CS, Hsieh MC

Received 31 January 2020

Accepted for publication 13 May 2020

Published 17 June 2020 Volume 2020:12 Pages 4645—4665

DOI https://doi.org/10.2147/CMAR.S247876

Checked for plagiarism Yes

Review by Single-blind

Peer reviewer comments 2

Editor who approved publication: Dr Eileen O'Reilly


Ya-Hui Chen,1,2 Yi-Chun Chen,1 Chi-Chen Lin,3– 5 Yao-Peng Hsieh,6– 8 Chien-Sheng Hsu,9 Ming-Chia Hsieh1,10

1Diabetes Research Laboratory, Department of Research, Changhua Christian Hospital, Changhua, Taiwan; 2Institute of Biochemistry and Biotechnology, Chung Shan Medical University, Taichung, Taiwan; 3Institute of Biomedical Science, National Chung-Hsing University, Taichung, Taiwan; 4Department of Health and Nutrition, Asia University, Taichung, Taiwan; 5Department of Medical Research, China Medical University Hospital, Taichung, Taiwan; 6Division of General Internal Medicine, Department of Internal Medicine, Changhua Christian Hospital, Changhua, Taiwan; 7School of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; 8School of Medicine, Chung Shan Medical University, Taichung, Taiwan; 9Frontier Molecular Medical Research Center in Children, Changhua Christian Children Hospital, Changhua, Taiwan; 10Intelligent Diabetes Metabolism and Exercise Center, China Medical University Hospital, Taichung, Taiwan

Correspondence: Ming-Chia Hsieh Email D94750@mail.cmuh.org.tw

Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with an overall 5-year survival rate of 9.3%, and this malignancy is expected to become the second leading cause of cancer-related death by 2030. Gemcitabine resistance develops within weeks of PDAC patient’s chemotherapeutic initiation. Statins, including pitavastatin, have been indicated to have anticancer effects in numerous human cancer cell lines. Thus, in this study, we hypothesized that a combination of gemcitabine and pitavastatin may have a greater anticancer effect than gemcitabine alone on the human pancreatic carcinoma cell line MIA PaCa-2.
Methods: The anticancer effects of gemcitabine with pitavastatin were evaluated using human MIA PaCa-2 cell line in vitro and in vivo Balb/c murine xenograft tumor model. Cell viability was assessed with CCK-8, and cell migration was stained by crystal violet. Cell cycle distribution, apoptosis and mitochondrial membrane potential were examined by flow cytometry. Activation of drug transporters (hENTs, hCNTs), intracellular drug activating (dCK) and inhibition of inactivating enzymes (RRMs) pathways were assessed by Western blotting analysis. Molecular mechanisms and signaling pathways of apoptosis, necrosis and autophagy also were assessed by Western blotting.
Results: We observed that gemcitabine and pitavastatin synergistically suppressed the proliferation of MIA PaCa-2 cells through causing sub-G1 and S phase cell cycle arrest. Activation of apoptosis/necrosis was confirmed by annexin V/propidium iodide double staining, which showed increasing levels of active caspase 3, cleaved poly(ADP-ribose) polymerase and the RIP1–RIP3–MLKL complex. Moreover, gemcitabine–pitavastatin-mediated S phase arrest downregulated cyclin A2/CDK2 and upregulated p21/p27 in MIA PaCa-2 cells. Furthermore, this combination improved drug cellular metabolism pathway, mitochondria function and activated autophagy as part of the cell death mechanism. In vivo, gemcitabine-pitavastatin effectively inhibited tumor growth in a nude mouse mode of Mia PaCa-2 xenografts without observed adverse effect.
Conclusion: Combined gemcitabine–pitavastatin may be an effective novel treatment option for pancreatic cancer.

Keywords: synergistic anticancer, gemcitabine, pitavastatin, pancreatic cancer, MIA PaCa-2

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