Econazole Nitrate Inhibits PI3K Activity and Promotes Apoptosis in Lung Cancer Cells

Overview

Journal Sci Rep

Specialty Science

Date 2017 Dec 23

PMID 29269744

Citations 14

Authors

Chao Dong

Runxiang Yang

Hongjian Li

Kunbin Ke

Chunxiang Luo

Fang Yang

Xi-Nan Shi

Ying Zhu

Xu Liu

Man-Hon Wong

Guimiao Lin

Xiaomei Wang

Kwong-Sak Leung

Hsiang-Fu Kung

Ceshi Chen

Marie Chia-Mi Lin

Affiliations

Soon will be listed here.

Abstract

The phosphatidylinositol-3-kinase (PI3K)/AKT signaling pathway plays a pivotal role in many cellular processes, including the proliferation, survival and differentiation of lung cancer cells. Thus, PI3K is a promising therapeutic target for lung cancer treatment. In this study, we applied free and open-source protein-ligand docking software, screened 3167 FDA-approved small molecules, and identified putative PI3Kα inhibitors. Among them, econazole nitrate, an antifungal agent, exhibited the highest activity in decreasing cell viability in pathological types of NSCLC cell lines, including H661 (large cell lung cancer) and A549 (adenocarcinoma). Econazole decreased the protein levels of p-AKT and Bcl-2, but had no effect on the phosphorylation level of ERK. It inhibited cell growth and promote apoptosis in a dose-dependent manner. Furthermore, the combination of econazole and cisplatin exhibited additive and synergistic effects in the H661 and A549 lung cancer cell lines, respectively. Finally, we demonstrated that econazole significantly suppressed A549 tumor growth in nude mice. Our findings suggest that econazole is a new PI3K inhibitor and a potential drug that can be used in lung cancer treatment alone or in combination with cisplatin.

Citing Articles

Nociceptive transient receptor potential ankyrin 1 (TRPA1) in sensory neurons are targets of the antifungal drug econazole.

Kasuya K, Takahashi K, Hashimoto M, Ohta T BMC Pharmacol Toxicol. 2024; 25(1):53.

PMID: 39169383 PMC: 11337588. DOI: 10.1186/s40360-024-00779-x.

Identification of 3-Aryl-1-benzotriazole-1-yl-acrylonitrile as a Microtubule-Targeting Agent (MTA) in Solid Tumors.

Zoroddu S, Sanna L, Bordoni V, Weidong L, Gadau S, Carta A Int J Mol Sci. 2024; 25(11).

PMID: 38891892 PMC: 11172098. DOI: 10.3390/ijms25115704.

The TRPV6 Calcium Channel and Its Relationship with Cancer.

Wang Y, Deng X, Zhang R, Lyu H, Xiao S, Guo D Biology (Basel). 2024; 13(3).

PMID: 38534438 PMC: 10968549. DOI: 10.3390/biology13030168.

Econazole selectively induces cell death in NF1-homozygous mutant tumor cells.

Lakes Y, Moye S, Mo J, Tegtmeyer M, Nehme R, Charlton M Cell Rep Med. 2023; 4(12):101309.

PMID: 38086379 PMC: 10772348. DOI: 10.1016/j.xcrm.2023.101309.

A drug repurposing screen for whipworms informed by comparative genomics.

Coghlan A, Partridge F, Duque-Correa M, Rinaldi G, Clare S, Seymour L PLoS Negl Trop Dis. 2023; 17(9):e0011205.

PMID: 37669291 PMC: 10503962. DOI: 10.1371/journal.pntd.0011205.

References

Curtin N, Szabo C . Therapeutic applications of PARP inhibitors: anticancer therapy and beyond. Mol Aspects Med. 2013; 34(6):1217-56. PMC: 3657315. DOI: 10.1016/j.mam.2013.01.006. View

Vanhaesebroeck B, Guillermet-Guibert J, Graupera M, Bilanges B . The emerging mechanisms of isoform-specific PI3K signalling. Nat Rev Mol Cell Biol. 2010; 11(5):329-41. DOI: 10.1038/nrm2882. View

Yamamoto H, Shigematsu H, Nomura M, Lockwood W, Sato M, Okumura N . PIK3CA mutations and copy number gains in human lung cancers. Cancer Res. 2008; 68(17):6913-21. PMC: 2874836. DOI: 10.1158/0008-5472.CAN-07-5084. View

Liu R, Li J, Zhang T, Zou L, Chen Y, Wang K . Itraconazole suppresses the growth of glioblastoma through induction of autophagy: involvement of abnormal cholesterol trafficking. Autophagy. 2014; 10(7):1241-55. PMC: 4203550. DOI: 10.4161/auto.28912. View

Dunlap J, Le C, Shukla A, Patterson J, Presnell A, Heinrich M . Phosphatidylinositol-3-kinase and AKT1 mutations occur early in breast carcinoma. Breast Cancer Res Treat. 2009; 120(2):409-18. DOI: 10.1007/s10549-009-0406-1. View

Huang J, Liu C, Chou C, Liu S, Hsu S, Chang H . Effects of econazole on Ca2+ levels in and the growth of human prostate cancer PC3 cells. Clin Exp Pharmacol Physiol. 2005; 32(9):735-41. DOI: 10.1111/j.1440-1681.2005.04254.x. View

Dumont A, Dumont S, Trent J . The favorable impact of PIK3CA mutations on survival: an analysis of 2587 patients with breast cancer. Chin J Cancer. 2012; 31(7):327-34. PMC: 3777497. DOI: 10.5732/cjc.012.10032. View

Huang Z, Wong C . Inexpensive Method for Selecting Receptor Structures for Virtual Screening. J Chem Inf Model. 2015; 56(1):21-34. DOI: 10.1021/acs.jcim.5b00299. View

Wang L, Hu H, Pan Y, Wang R, Li Y, Shen L . PIK3CA mutations frequently coexist with EGFR/KRAS mutations in non-small cell lung cancer and suggest poor prognosis in EGFR/KRAS wildtype subgroup. PLoS One. 2014; 9(2):e88291. PMC: 3922761. DOI: 10.1371/journal.pone.0088291. View

10.

Morris G, Huey R, Lindstrom W, Sanner M, Belew R, Goodsell D . AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J Comput Chem. 2009; 30(16):2785-91. PMC: 2760638. DOI: 10.1002/jcc.21256. View

11.

Li H, Leung K, Wong M, Ballester P . Improving AutoDock Vina Using Random Forest: The Growing Accuracy of Binding Affinity Prediction by the Effective Exploitation of Larger Data Sets. Mol Inform. 2016; 34(2-3):115-26. DOI: 10.1002/minf.201400132. View

12.

Cogswell S, Berger S, Waterhouse D, Bally M, Wasan E . A parenteral econazole formulation using a novel micelle-to-liposome transfer method: in vitro characterization and tumor growth delay in a breast cancer xenograft model. Pharm Res. 2006; 23(11):2575-85. DOI: 10.1007/pl00022054. View

13.

Ueda Y, Igishi T, Hashimoto K, Suyama H, Araki K, Sumikawa T . Synergistic cell growth inhibition by the combination of amrubicin and Akt-suppressing tyrosine kinase inhibitors in small cell lung cancer cells: implication of c-Src and its inhibitor. Int J Oncol. 2009; 34(3):689-96. DOI: 10.3892/ijo_00000195. View

14.

Najid A, Ratinaud M . Comparative studies of steroidogenesis inhibitors (econazole, ketoconazole) on human breast cancer MCF-7 cell proliferation by growth experiments, thymidine incorporation and flow cytometric DNA analysis. Tumori. 1991; 77(5):385-90. DOI: 10.1177/030089169107700504. View

15.

Bao R, Lai C, Wang D, Qu H, Yin L, Zifcak B . Targeting heat shock protein 90 with CUDC-305 overcomes erlotinib resistance in non-small cell lung cancer. Mol Cancer Ther. 2009; 8(12):3296-306. DOI: 10.1158/1535-7163.MCT-09-0538. View

16.

Marcondes M, Sola-Penna M, Zancan P . Clotrimazole potentiates the inhibitory effects of ATP on the key glycolytic enzyme 6-phosphofructo-1-kinase. Arch Biochem Biophys. 2010; 497(1-2):62-7. DOI: 10.1016/j.abb.2010.03.013. View

17.

Li H, Leung K, Ballester P, Wong M . istar: a web platform for large-scale protein-ligand docking. PLoS One. 2014; 9(1):e85678. PMC: 3901662. DOI: 10.1371/journal.pone.0085678. View

18.

Sun J, Yu C, Zhao X, Wang Y, Jiang S, Gong X . Econazole Nitrate Induces Apoptosis in MCF-7 Cells via Mitochondrial and Caspase Pathways. Iran J Pharm Res. 2015; 13(4):1327-34. PMC: 4232799. View

19.

Najafov A, Shpiro N, Alessi D . Akt is efficiently activated by PIF-pocket- and PtdIns(3,4,5)P3-dependent mechanisms leading to resistance to PDK1 inhibitors. Biochem J. 2012; 448(2):285-95. DOI: 10.1042/BJ20121287. View

20.

Ho Y, Wu C, Chou H, Wang Y, Tseng H, Chen C . Molecular mechanisms of econazole-induced toxicity on human colon cancer cells: G0/G1 cell cycle arrest and caspase 8-independent apoptotic signaling pathways. Food Chem Toxicol. 2005; 43(10):1483-95. DOI: 10.1016/j.fct.2005.04.002. View