hERG potassium channels mediate the anti-proliferative effects of brucine and strychnine on cancer cells

doi:10.13418/j.issn.1001-165x.2023.6.10

PDF(5144 KB)

Chinese Journal of Clinical Anatomy ›› 2023, Vol. 41 ›› Issue (6) : 684-691. DOI: 10.13418/j.issn.1001-165x.2023.6.10

hERG potassium channels mediate the anti-proliferative effects of brucine and strychnine on cancer cells

Zeng Xian, Zhou Ying, Yin Yanan, Xie Ting, Li Shuji, Yuan Chunhua*

Author information +

History +

Abstract

Objective To investigate the anti-tumor effect of brucine and strychnine based on their blockage of hERG channels. Methods The vector-transfected and hERG-transfected CHO cells were constructed by Lipofection and selective medium. After treated with brucine and its structural analogues for 24 h, 48 h, and 72 h, the effect in cell proliferation in cancer cells were evaluated by using CCK8 assay. After treated with brucine and its structural analogues for 48 h, the effect in cell proliferation in hERG-transfected CHO cells were evaluated by using CCK8 assay, and the vector-transfected CHO cells were as control. Flow cytometry was used to detect the cell cycle arrest of brucine and strychnine on HT29 and A549 cells. Western blot was used to detect the levels of hERG expression in HT29, PC9, and A549 cells. Results Brucine and strychnine time and dose-dependently inhibited the proliferation of HT29, PC9, and A549 cell lines, and the inhibitory potency was positively correlated with the expression level of hERG protein. Faint anti-proliferation activity was detected at high concentration for brucine N-oxide and strychnine N-oxide which showed weak inhibitory effect on hERG channel and tumor cell only at high concentration. Furthermore, brucine induced more growth suppression on the hERG-transfected CHO cells, when compared with vector-transfected CHO cells. Brucine and strychnine induced G0/G1cell cycle arrest in HT29 cells, and showed no significant effect on the cell cycle of A549 cells. Brucine showed no significant effects on hERG protein expression in the three cell lines. Conclusions Brucine and strychnine displayed their anti-tumor effect may through blocking hERG channels. This study may provide important clues for using the potential pharmacologic effects of hERG inhibitors in cancer treatment.

Key words

Nux Vomica; / / Anti-tumor; / / hERG expression; / / hERG blocker

Cite this article

EndNote

Ris (Procite)

Bibtex

Download Citations

Zeng Xian, Zhou Ying, Yin Yanan, Xie Ting, Li Shuji, Yuan Chunhua. hERG potassium channels mediate the anti-proliferative effects of brucine and strychnine on cancer cells[J]. Chinese Journal of Clinical Anatomy. 2023, 41(6): 684-691 https://doi.org/10.13418/j.issn.1001-165x.2023.6.10

References

[1] Guo R, Wang T, Zhou G, et al. Botany, phytochemistry, pharmacology and toxicity of strychnos nux-vomica l.: a review[J]. Am J Chin Med, 2018, 46(1): 1-23. DOI: 10.1142/S0192415X18500015.
[2] Hong B, Grzech D, Caputi L, et al. Biosynthesis of strychnine[J]. Nature, 2022, 607(7919): 617-622. DOI: 10.1038/s41586-022-04950-4.
[3] Zlotos DP, Mandour YM, Jensen AA. Strychnine and its mono- and dimeric analogues: a pharmaco-chemical perspective[J]. Nat Prod Rep, 2022, 39(10): 1910-1937. DOI: 10.1039/d1np00079a.
[4] Gao Y, Xin D, Liang XD, et al. Effect of a combination of Atractylodes macrocephala extract with strychnine on the TLR4/NF-κB/NLRP3 pathway in MH7A cells[J]. Exp Ther Med, 2023, 25(2): 91. DOI: 10.3892/etm.2023.11791.
[5] Li M, Li P, Zhang M, et al. Brucine suppresses breast cancer metastasis via inhibiting epithelial mesenchymal transition and matrix metalloproteinases expressions[J]. Chin J Integr Med, 2018, 24(1): 40-46. DOI: 10.1007/s11655-017-2805-1.
[6] Qin J, Yang L, Sheng X, et al. Antitumor effects of brucine immol/Luno-nanoparticles on hepatocellular carcinoma in vivo[J]. Oncol Lett, 2018, 15: 6137-6146. DOI: 10.3892/ol.2018.8168.
[7] Xu MR, Wei PF, Suo MZ, et al. Brucine suppresses vasculogenic mimicry in human triple-negative breast cancer cell line MDA-MB-231[J]. Biomed Res Int, 2019, 2019: 6543230. DOI: 10.1155/2019/6543230.
[8] Jones DK, Liu F, Vaidyanathan R, et al. hERG 1b is critical for human cardiac repolarization[J]. Proc Natl Acad Sci U S A, 2014, 111(50): 18073-18077. DOI: 10.1073/pnas.1414945111.
[9] Vandenberg JI, Perry MD, Perrin MJ, et al. hERG K(+) channels: structure, function, and clinical significance[J]. Physiol Rev, 2012, 92(3): 1393-1478. DOI: 10.1152/physrev.00036.2011.
[10]Zheng Z, Song Y. Integrated analysis of the voltage-gated potassium channel-associated gene KCNH2 across cancers[J]. BMC Bioinformatics, 2023, 24(1): 51. DOI: 10.1186/s12859-023-05180-9.
[11]He S, Moutaoufik MT, Islam S, et al. HERG channel and cancer: A mechanistic review of carcinogenic processes and therapeutic potential[J]. Biochim Biophys Acta Rev Cancer, 2020, 1873(2): 188355. DOI: 10.1016/j.bbcan.2020.188355.
[12] Jehle J, Schweizer PA, Katus HA, et al. Novel roles for hERG K(+) channels in cell proliferation and apoptosis[J]. Cell Death Dis, 2011, 2(8): e193. DOI: 10.1038/cddis.2011.77.
[13] Shugg T, Dave N, Amarh E, et al. Letrozole targets the human ether-a-go-go-related gene potassium current in glioblastoma[J]. Basic Clin Pharmacol Toxicol, 2021, 128(3): 357-365. DOI: 10.1111/bcpt.13515.
[14]Yuan C, Luo Z, Zhou Y, et al. Removal of hERG potassium channel affinity through introduction of an oxygen atom: Molecular insights from structure-activity relationships of strychnine and its analogs[J]. Toxicol Appl Pharmacol, 2018, 360: 109-119. DOI: 10.1016/j.taap.2018.09.042.
[15]Trudeau MC, Warmke JW, Ganetzky B, et al. HERG, a human inward rectifier in the voltage-gated potassium channel family[J]. Science, 1995, 269(5220): 92-95. DOI: 10.1126/science.7604285.
[16] Chen J, Wang X, Qu YG, et al. Analgesic and anti-inflammol/Latory activity and pharmacokinetics of alkaloids from seeds of Strychnos nux-vomica after transdermal administration: effect of changes in alkaloid composition[J]. J Ethnopharmacol, 2012, 139(1): 181-188. DOI: 10.1016/j.jep.2011.10.038.
[17] Ji N, Li J, Wei Z, et al. Effect of celastrol on growth inhibition of prostate cancer cells through the regulation of hERG channel in vitro[J]. Biomed Res Int, 2015, 2015: 308475. DOI: 10.1155/2015/308475.
[18] King KL, Cidlowski JA. Cell cycle regulation and apoptosis[J]. Annu Rev Physiol, 1998,60: 601-617. DOI: 10.1146/annurev.physiol.60. 1.601.
[19] Owa T, Yoshino H, Yoshimatsu K, et al. Cell cycle regulation in the G1 phase: a promising target for the development of new chemotherapeutic anticancer agents[J]. Curr Med Chem, 2001, 8(12): 1487-1503. DOI: 10.2174/0929867013371996.
[20] Wei X, Sun H, Yan H, et al. ZC88, a novel 4-amino piperidine analog, inhibits the growth of neuroblastoma cells through blocking hERG potassium channel[J]. Cancer Biol Ther, 2013, 14(5): 450-457. DOI: 10.4161/cbt.24423.
[21] Vaddi DR, Piao L, Khan SA, et al. Hypoxia induced hERG trafficking defect linked to cell cycle arrest in SH-SY5Y cells[J]. PLoS One, 2019, 14(4): e0215905. DOI: 10.1371/journal.pone.0215905.
[22] Arcangeli A, Bianchi L, Becchetti A, et al. A novel inward-rectifying K+ current with a cell-cycle dependence governs the resting potential of mammol/Lalian neuroblastoma cells[J]. J Physiol, 1995, 489(Pt 2): 455-471. DOI: 10.1113/jphysiol.1995.sp021065.
[23] Palme D, Misovic M, Ganser K, et al. herg k+ channels promote survival of irradiated leukemia cells[J]. Front Pharmacol, 2020, 11: 489. DOI: 10.3389/fphar.2020.00489.
[24] Redfern WS, Carlsson L, Davis AS, et al. Relationships between preclinical cardiac electrophysiology, clinical QT interval prolongation and torsade de pointes for a broad range of drugs: evidence for a provisional safety margin in drug development[J]. Cardiovasc Res, 2003, 58: 32-45. DOI: 10.1016/s0008-6363(02)00846-5.
[25] Ismail TA, Shehata TM, Mohamed DI, et al. Quality by design for development, optimization and characterization of brucine ethosomal gel for skin cancer delivery[J]. Molecules, 2021, 26(11): 3454. DOI: 10.3390/molecules26113454.
[26] 刘丹, 于佳. 马钱子碱mPEG-PLGA纳米粒的构建与体外抗肿瘤细胞活性研究[J]. 沈阳药科大学学报, 2021, (11): 1133-1138. DOI: 10.14066/j.cnki.cn21-1349/r.2020.0248.
[27] Arcangeli A, Becchetti A. hERG channels: from antitargets to novel targets for cancer therapy[J]. Clin Cancer Res, 2017, 23(1): 3-5. DOI: 10.1158/1078-0432.CCR-16-2322.
[28] Pointer KB, Clark PA, Eliceiri KW, et al. Administration of non-torsadogenic human ether-à-go-go-related gene inhibitors is associated with better survival for high hERG-expressing glioblastoma patients[J]. Clin Cancer Res, 2017, 23(1): 73-80. DOI: 10.1158/1078-0432.CCR-15-3169.