Generic placeholder image

Current Molecular Medicine


ISSN (Print): 1566-5240
ISSN (Online): 1875-5666

Research Article

Hydroquinidine Demonstrates Remarkable Antineoplastic Effects on Non-small Cell Lung Cancer Cells

Author(s): Mervenur Yavuz and Turan Demircan*

Volume 24, Issue 9, 2024

Published on: 20 September, 2023

Page: [1159 - 1168] Pages: 10

DOI: 10.2174/1566524023666230817115937

Price: $65


Background: Despite recent progress in drug development, lung cancer remains a complex disease that poses a major public health issue worldwide, and new therapeutic strategies are urgently needed because of the failure of standard treatments. Ion channels play a critical role in various cellular processes that regulate cell proliferation, differentiation, and cell death.

Objectives: The potential of ion channel modulators as tumor growth suppressors has been highlighted in recent studies. Therefore, we hypothesized that hydroquinidine (HQ), a previously understudied potassium channel modulator, might have anticarcinogenic activity against A549 cells.

Methods: The anticancer potential of HQ was investigated using various wellestablished in vitro assays.

Results: HQ significantly decreased colony formation and tumorigenicity and exhibited a significant anti-migratory effect in A549 cells. Our results demonstrated that HQ significantly inhibited the growth of cancer cells by decreasing the proliferation rate while increasing cell death. The altered gene expression profile in response to treatment with HQ was consistent with the observed cellular effects. Incubation of cells with HQ resulted in the downregulation of genes involved in cell division and survival, while genes promoting cell cycle arrest and apoptosis were upregulated.

Conclusion: Our findings suggest that HQ has the potential to limit lung cancer growth as a novel potent anticarcinogenic agent. However, more investigations are needed to gain further insight into the mechanism of action of HQ and to evaluate its efficacy in invivo models.

Keywords: Ion channel blocker, hydroquinidine, lung cancer, anti-cancer agent, drug repurposing.

Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin 2019; 69(1): 7-34.
[] [PMID: 30620402]
Bittner N, Ostoros G, Géczi L. New treatment options for lung adenocarcinoma--in view of molecular background. Pathol Oncol Res 2014; 20(1): 11-25.
[] [PMID: 24306880]
Goldstraw P, Chansky K, Crowley J, et al. The IASLC lung cancer staging project: Proposals for revision of the tnm stage groupings in the forthcoming (eighth) edition of the tnm classification for lung cancer. J Thorac Oncol 2016; 11(1): 39-51.
[] [PMID: 26762738]
Goodwin J, Neugent ML, Kim JW. Lung squamous cell carcinoma exhibits a targetable glucose dependency unique among non-small cell lung cancers. Mol Cell Oncol 2017; 4(5): e1364211.
[] [PMID: 29057314]
Calles A, Aguado G, Sandoval C, Álvarez R. The role of immunotherapy in small cell lung cancer. Clin Transl Oncol 2019; 21(8): 961-76.
[] [PMID: 30637710]
Litan A, Langhans SA. Cancer as a channelopathy: Ion channels and pumps in tumor development and progression. Front Cell Neurosci 2015; 9: 86.
[] [PMID: 25852478]
Bortner CD, Cidlowski JA. Ion channels and apoptosis in cancer. Philos Trans R Soc Lond B Biol Sci 2014; 369(1638): 20130104.
[] [PMID: 24493752]
Kunzelmann K. Ion channels and cancer. J Membr Biol 2005; 205(3): 159-73.
[] [PMID: 16362504]
Schwab A, Stock C. Ion channels and transporters in tumour cell migration and invasion. Philos Trans R Soc Lond B Biol Sci 2014; 369(1638): 20130102.
[] [PMID: 24493750]
Tomasini P, Walia P, Labbe C, Jao K, Leighl NB. Targeting the KRAS pathway in non-small cell lung cancer. Oncologist 2016; 21(12): 1450-60.
[] [PMID: 27807303]
Chen S, Jiang M, Zhen Y. HERG K+ channel expression-related chemosensitivity in cancer cells and its modulation by erythromycin. Cancer Chemother Pharmacol 2005; 56(2): 212-20.
[] [PMID: 15812674]
Liu H, Huang J, Peng J, et al. Upregulation of the inwardly rectifying potassium channel Kir2.1 (KCNJ2) modulates multidrug resistance of small-cell lung cancer under the regulation of miR-7 and the Ras/MAPK pathway. Mol Cancer 2015; 14(1): 59.
[] [PMID: 25880778]
Christensen SB. Natural products that changed society. Biomedicines 2021; 9(5): 472.
[] [PMID: 33925870]
Kraliz D, Bhattacharya A, Singh S. Blockade of the delayed rectifier potassium current in drosophila by quinidine and related compounds. J Neurogenet 1998; 12(1): 25-39.
[] [PMID: 9666899]
Revenko SV, Khodorov BI, Shapovalova LM. Quinidine blocking of sodium and potassium channels in myelinated nerve fibers. Neurophysiology 1983; 14(3): 244-50.
[] [PMID: 6287317]
Hermida JS, Denjoy I, Clerc J, et al. Hydroquinidine therapy in brugada syndrome. J Am Coll Cardiol 2004; 43(10): 1853-60.
[] [PMID: 15145111]
Mazzanti A, Maragna R, Vacanti G, et al. Hydroquinidine prevents life-threatening arrhythmic events in patients with short QT syndrome. J Am Coll Cardiol 2017; 70(24): 3010-5.
[] [PMID: 29241489]
Akhtar N, Pradhan N, Barik GK, et al. Quinine-based semisynthetic ion transporters with potential antiproliferative activities. ACS Appl Mater Interfaces 2020; 12(23): 25521-33.
[] [PMID: 32425038]
Liu W, Qi Y, Liu L, Tang Y, Wei J, Zhou L. Suppression of tumor cell proliferation by quinine via the inhibition of the tumor necrosis factor receptor-associated factor 6-AKT interaction. Mol Med Rep 2016; 14(3): 2171-9.
[] [PMID: 27430155]
Ru Q, Tian X, Pi MS, et al. Voltage-gated K+ channel blocker quinidine inhibits proliferation and induces apoptosis by regulating expression of microRNAs in human glioma U87-MG cells. Int J Oncol 2015; 46(2): 833-40.
[] [PMID: 25420507]
Demircan T, Yavuz M. The effect of hydroquinidine on proliferation and apoptosis of TMZ-sensitive and -resistant GBM Cells. Anticancer Agents Med Chem 2023; 23(8): 938-52.
[] [PMID: 36437723]
Yavuz M, Demircan T. A potent ion channel blocker, hydroquinidine, exhibits strong anti-cancer activity on colon, pancreatic, and hepatocellular cancer cells. Mol Biol Rep 2023; 50(3): 2611-21.
[] [PMID: 36633730]
Mervenur Yavuz M, Şahin B, Baykal AT, Demircan T. Hydroquinidine displays a significant anti-carcinogenic activity in breast and ovarian cancer cells via inhibiting cellcycle and stimulating apoptosis. Turk J Biol 2023; 47(1): 44-60.
Bulk E, Todesca LM, Schwab A. Ion channels in lung cancer. Rev Physiol Biochem Pharmacol 2020; 181: 57-79.
[] [PMID: 32772273]
Ritz C, Baty F, Streibig JC, Gerhard D. Dose-response analysis using R. PLoS One 2015; 10(12): e0146021.
[] [PMID: 26717316]
Wickham H. ggplot2. Wiley Interdiscip Rev Comput Stat 2011; 3(2): 180-5.
Lang F, Stournaras C. Ion channels in cancer: Future perspectives and clinical potential. Philos Trans R Soc Lond B Biol Sci 2014; 369(1638): 20130108.
[] [PMID: 24493756]
Qi Y, Pradipta AR, Li M, et al. Cinchonine induces apoptosis of HeLa and A549 cells through targeting TRAF6. J Exp Clin Cancer Res 2017; 36(1): 35.
[] [PMID: 28231796]
Lin SY, Chang HH, Lai YH, et al. Digoxin suppresses tumor malignancy through inhibiting multiple src-related signaling pathways in non-small cell lung cancer. PLoS One 2015; 10(5): e0123305.
[] [PMID: 25955608]
Schneider NFZ, Menegaz D, Dagostin ALA, et al. Cytotoxicity of glucoevatromonoside alone and in combination with chemotherapy drugs and their effects on Na+,K+-ATPase and ion channels on lung cancer cells. Mol Cell Biochem 2021; 476(4): 1825-48.
[] [PMID: 33459980]
Xiong W, Fan H, Zeng Q, Deng Z, Li G, Lu W. The anticancer effects of FS48 from salivary glands of on NCI-H460 cells its blockage of voltage-gated K channels. Acta Pharm 2023; 73(1): 145-55.
[] [PMID: 36692462]
Li D, Tong Q, Lian Y, et al. Inhibition of lncRNA KCNQ1OT1 improves apoptosis and chemotherapy drug response in small cell lung cancer by tgf-β1 mediated epithelial-to-mesenchymal transition. Cancer Res Treat 2021; 53(4): 1042-56.
[] [PMID: 33705625]
Girault A, Privé A, Trinh NTN, et al. Identification of KvLQT1 K+ channels as new regulators of non-small cell lung cancer cell proliferation and migration. Int J Oncol 2014; 44(3): 838-48.
[] [PMID: 24366043]
Glassmeier G, Hempel K, Wulfsen I, Bauer CK, Schumacher U, Schwarz JR. Inhibition of HERG1 K+ channel protein expression decreases cell proliferation of human small cell lung cancer cells. Pflugers Arch 2012; 463(2): 365-76.
[] [PMID: 22075718]
Xu P, Mo X, Xia R, et al. KCNN4 promotes the progression of lung adenocarcinoma by activating the AKT and ERK signaling pathways. Cancer Biomark 2021; 31(2): 187-201.
[] [PMID: 33896824]
Roninson IB. Tumor cell senescence in cancer treatment. Cancer Res 2003; 63(11): 2705-15.
[PMID: 12782571]
Schmitt CA, Fridman JS, Yang M, et al. A senescence program controlled by p53 and p16INK4a contributes to the outcome of cancer therapy. Cell 2002; 109(3): 335-46.
[] [PMID: 12015983]
Chang BD, Xuan Y, Broude EV, et al. Role of p53 and p21waf1/cip1 in senescence-like terminal proliferation arrest induced in human tumor cells by chemotherapeutic drugs. Oncogene 1999; 18(34): 4808-18.
[] [PMID: 10490814]
Lee JH, Park JW, Byun JK, et al. Silencing of voltage-gated potassium channel KV9.3 inhibits proliferation in human colon and lung carcinoma cells. Oncotarget 2015; 6(10): 8132-43.
[] [PMID: 25924237]
Mu D, Chen L, Zhang X, et al. Genomic amplification and oncogenic properties of the KCNK9 potassium channel gene. Cancer Cell 2003; 3(3): 297-302.
[] [PMID: 12676587]
Innamaa A, Jackson L, Asher V, et al. Expression and prognostic significance of the oncogenic K2P potassium channel KCNK9 (TASK-3) in ovarian carcinoma. Anticancer Res 2013; 33(4): 1401-8.
[PMID: 23564779]
Sun H, Luo L, Lal B, et al. A monoclonal antibody against KCNK9 K+ channel extracellular domain inhibits tumour growth and metastasis. Nat Commun 2016; 7(1): 10339.
[] [PMID: 26842342]
Zúñiga R, Valenzuela C, Concha G, Brown N, Zúñiga L. TASK-3 downregulation triggers cellular senescence and growth inhibition in breast cancer cell lines. Int J Mol Sci 2018; 19(4): 1033.
[] [PMID: 29596383]
Lu X, Li K, Yang J. Potassium voltage-gated channel subfamily D member 2 induces an aggressive phenotype in lung adenocarcinoma. Neoplasma 2021; 68(1): 135-43.
Park SH, Park SJ, Kim JO, et al. Down-regulation of survivin by nemadipine-A sensitizes cancer cells to TRAIL-Induced apoptosis. Biomol Ther 2013; 21(1): 29-34.
[] [PMID: 24009855]
Shahriyar SA, Seo SU, Min K, et al. Upregulation of DR5 and downregulation of survivin by IITZ-01, lysosomotropic autophagy inhibitor, potentiates TRAIL-mediated apoptosis in renal cancer cells via ubiquitin-proteasome pathway. Cancers 2020; 12(9): 2363.
[] [PMID: 32825566]
Wang M, Chen S, Ao D. Targeting DNA repair pathway in cancer: Mechanisms and clinical application. MedComm 2021; 2(4): 654-91.
[] [PMID: 34977872]
Zheng LW, Shao JH, Zhao BX, Miao JY. Synthesis of novel pyrazolo[1,5- a]pyrazin-4(5 H)-one derivatives and their inhibition against growth of A549 and H322 lung cancer cells. Bioorg Med Chem Lett 2011; 21(13): 3909-13.
[] [PMID: 21640587]
Zhang JH, Fan CD, Zhao BX, et al. Synthesis and preliminary biological evaluation of novel pyrazolo[1,5-a]pyrazin-4(5H)-one derivatives as potential agents against A549 lung cancer cells. Bioorg Med Chem 2008; 16(24): 10165-71.
[] [PMID: 19013820]
Abd-Ella AA, Metwally SA, ul-Malik MAA, et al. A review on recent advances for the synthesis of bioactive pyrazolinone and pyrazolidinedione derivatives. Curr Chem Lett 2022; 11(2): 157-72.

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy