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

doi:10.2147/CMAR.S247876

中山醫學大學機構典藏 CSMUIR > 中山醫學大學研究成果 > 期刊論文 > Item 310902500/24806

Please use this identifier to cite or link to this item: https://ir.csmu.edu.tw:8080/ir/handle/310902500/24806

Title:	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
Keywords:	synergistic anticancer;gemcitabine;pitavastatin;pancreatic cancer;MIA PaCa-2
Date:	2020
Issue Date:	2022-08-09T08:08:17Z (UTC)
Publisher:	DOVE MEDICAL PRESS LTD
ISSN:	1179-1322
Abstract:	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-pitavastatinmediated 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.
URI:	http://dx.doi.org/10.2147/CMAR.S247876 https://www.webofscience.com/wos/woscc/full-record/WOS:000540416000001 https://ir.csmu.edu.tw:8080/handle/310902500/24806
Relation:	CANCER MANAGEMENT AND RESEARCH ,2020 ,v12 ,p4645-4665
Appears in Collections:	[中山醫學大學研究成果] 期刊論文

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