Generic placeholder image

Current Pharmaceutical Design


ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

Research Article

Nitidine Chloride Triggers Autophagy and Apoptosis of Ovarian Cancer Cells through Akt/mTOR Signaling Pathway

Author(s): Chaoqun Lian, Yinlong Huang, Ping Hu, Yuncheng Cao, Zhiqiang Zhang, Fan Feng* and Jing Zhang*

Volume 29, Issue 19, 2023

Published on: 26 June, 2023

Page: [1524 - 1534] Pages: 11

DOI: 10.2174/1381612829666230614154847

open access plus


Objective: Ovarian cancer (OC) is the eighth most common cancer with high mortality in women worldwide. Currently, compounds derived from Chinese herbal medicine have provided a new angle for OC treatment.

Methods: In this study, the cell proliferation and migration of ovarian cancer A2780/SKOV3 cells were inhibited after being treated with nitidine chloride (NC) by using MTT and Wound-Healing Assay. Flow cytometry analysis indicated NC-induced apoptosis of ovarian cancer cells, and AO and MDC staining showed that NC treatment induced the appearance of autophagosomes and autophagic lysosomes in ovarian cancer cells.

Results: Through the autophagy inhibition experiment of chloroquine, it was proved that NC significantly further promoted apoptosis in ovarian cancer cells. Furthermore, NC proved that it could significantly decrease the expression of autophagy-related genes such as Akt, mTOR, P85 S6K, P70 S6K, and 4E-BP1.

Conclusion: Therefore, we suggest that NC could trigger autophagy and apoptosis of ovarian cancer cells through Akt/mTOR signaling pathway, and NC may potentially be a target for chemotherapy against ovarian cancer.

Keywords: Ovarian cancer, nitidine chloride, cell autophagy, cell proliferation, cell apoptosis, Akt/mTOR pathway.

Biller VS, Leitzmann MF, Sedlmeier AM, Berger FF, Ortmann O, Jochem C. Sedentary behaviour in relation to ovarian cancer risk: A systematic review and meta-analysis. Eur J Epidemiol 2021; 36(8): 769-80.
[] [PMID: 33492550]
Shaik B, Zafar T, Balasubramanian K, Gupta SP. An overview of ovarian cancer: Molecular processes involved and development of target-based chemotherapeutics. Curr Top Med Chem 2021; 21(4): 329-46.
[] [PMID: 33183204]
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018; 68(6): 394-424.
[] [PMID: 30207593]
Zhang Y, Cao S, Zhuang C, et al. ERCC1 rs11615 polymorphism and chemosensitivity to platinum drugs in patients with ovarian cancer: A systematic review and meta-analysis. J Ovarian Res 2021; 14(1): 80.
[] [PMID: 34148553]
Friedlander M, Matulonis U, Gourley C, et al. Long-term efficacy, tolerability and overall survival in patients with platinum-sensitive, recurrent high-grade serous ovarian cancer treated with maintenance olaparib capsules following response to chemotherapy. Br J Cancer 2018; 119(9): 1075-85.
[] [PMID: 30353045]
Qin Y, Li W, Long Y, Zhan Z. Relationship between p-cofilin and cisplatin resistance in patients with ovarian cancer and the role of p-cofilin in prognosis. Cancer Biomark 2019; 24(4): 469-75.
[] [PMID: 30932883]
Atanasov AG, Zotchev SB, Dirsch VM, Supuran CT. Natural products in drug discovery: advances and opportunities. Nat Rev Drug Discov 2021; 20(3): 200-16.
[] [PMID: 33510482]
Xu Z, Eichler B, Klausner EA, Duffy-Matzner J, Zheng W. Lead/drug discovery from natural resources. Molecules 2022; 27(23): 8280.
[] [PMID: 36500375]
Ge S, Xing Q, Zhang A, Wang Y. Effect of traditional Chinese medicine (TCM) on survival, quality of life, and immune function in patients with ovarian carcinoma. Medicine 2021; 100(2): e23904.
[] [PMID: 33466133]
Wang S, Fu JL, Hao HF, Jiao YN, Li PP, Han SY. Metabolic reprogramming by traditional Chinese medicine and its role in effective cancer therapy. Pharmacol Res 2021; 170: 105728.
[] [PMID: 34119622]
Efferth T, Oesch F. Repurposing of plant alkaloids for cancer therapy: Pharmacology and toxicology. Semin Cancer Biol 2021; 68: 143-63.
[] [PMID: 31883912]
Fang Z, Tang Y, Jiao W, et al. Nitidine chloride inhibits renal cancer cell metastasis via suppressing AKT signaling pathway. Food Chem Toxicol 2013; 60: 246-51.
[] [PMID: 23911800]
Li C, Wang J, Ma R, et al. Natural-derived alkaloids exhibit great potential in the treatment of ulcerative colitis. Pharmacol Res 2022; 175: 105972.
[] [PMID: 34758401]
Cesari I, Grisoli P, Paolillo M, Milanese C, Massolini G, Brusotti G. Isolation and characterization of the alkaloid Nitidine responsible for the traditional use of Phyllanthus muellerianus (Kuntze) Excell stem bark against bacterial infections. J Pharm Biomed Anal 2015; 105: 115-20.
[] [PMID: 25546028]
Lu Q, Ma R, Yang Y, Mo Z, Pu X, Li C. Zanthoxylum nitidum (Roxb.) DC: Traditional uses, phytochemistry, pharmacological activities and toxicology. J Ethnopharmacol 2020; 260: 112946.
[] [PMID: 32492492]
Cui Y, Wu L, Cao R, et al. Antitumor functions and mechanisms of nitidine chloride in human cancers. J Cancer 2020; 11(5): 1250-6.
[] [PMID: 31956371]
Okagu IU, Ndefo JC, Aham EC, Udenigwe CC. Zanthoxylum species: A comprehensive review of traditional uses, phytochemistry, pharmacological and nutraceutical applications. Molecules 2021; 26(13): 4023.
[] [PMID: 34209371]
Khan H, Hadda TB, Touzani R. Diverse therapeutic potential of nitidine, a comprehensive review. Curr Drug Metab 2018; 19(12): 986-91.
[] [PMID: 29956622]
Lu Q, Luo S, Shi Z, Yu M, Guo W, Li C. Nitidine chloride, a benzophenanthridine alkaloid from Zanthoxylum nitidum (Roxb.) DC., exerts multiple beneficial properties, especially in tumors and inflammation-related diseases. Front Pharmacol 2022; 13: 1046402.
[] [PMID: 36506558]
Chen S, Yang L, Feng J. Nitidine chloride inhibits proliferation and induces apoptosis in ovarian cancer cells by activating the Fas signalling pathway. J Pharm Pharmacol 2018; 70(6): 778-86.
[] [PMID: 29516498]
Avila-Carrasco L, Majano P, Sánchez-Toméro JA, et al. Natural plants compounds as modulators of epithelial-to-mesenchymal transition. Front Pharmacol 2019; 10: 715.
[] [PMID: 31417401]
Saburi A, Kahrizi MS, Naghsh N, et al. A comprehensive survey into the role of microRNAs in ovarian cancer chemoresistance; an updated overview. J Ovarian Res 2022; 15(1): 81.
[] [PMID: 35799305]
Moufarrij S, Dandapani M, Arthofer E, et al. Epigenetic therapy for ovarian cancer: promise and progress. Clin Epigenetics 2019; 11(1): 7.
[] [PMID: 30646939]
Ghoneum A, Afify H, Salih Z, Kelly M, Said N. Role of tumor microenvironment in ovarian cancer pathobiology. Oncotarget 2018; 9(32): 22832-49.
[] [PMID: 29854318]
Chan KKL, Yao TJ, Jones B, et al. The use of Chinese herbal medicine to improve quality of life in women undergoing chemotherapy for ovarian cancer: a double-blind placebo-controlled randomized trial with immunological monitoring. Ann Oncol 2011; 22(10): 2241-9.
[] [PMID: 21355071]
Peng X, Jia C, Chi H, et al. Efficacy and pharmacological mechanism of Poria cocos-based formulas combined with chemotherapy for ovarian cancer: A integrated systems pharmacology study. Front Pharmacol 2022; 13: 788810.
[] [PMID: 35401186]
Hussain I, Waheed S, Ahmad KA, Pirog JE, Syed V. Scutellaria baicalensis targets the hypoxia-inducible factor-1α and enhances cisplatin efficacy in ovarian cancer. J Cell Biochem 2018; 119(9): 7515-24.
[] [PMID: 29797601]
Wang S, Gao J, Li Q, et al. Study on the regulatory mechanism and experimental verification of icariin for the treatment of ovarian cancer based on network pharmacology. J Ethnopharmacol 2020; 262: 113189.
[] [PMID: 32736044]
Owen S, Ruge F, Gao Y, et al. ShenLingLan influences the attachment and migration of ovarian cancer cells potentially through the GSK3 pathway. Medicines 2017; 4(1): 10.
[] [PMID: 28930226]
Rivera D, Allkin R, Obón C, Alcaraz F, Verpoorte R, Heinrich M. What is in a name? The need for accurate scientific nomenclature for plants. J Ethnopharmacol 2014; 152(3): 393-402.
[] [PMID: 24374235]
Chinese Pharmacopeia 2020 Edition, I. Beijing: China Medical Science Press 2020; pp. 176-7.
Yang CH, Cheng MJ, Chiang MY, Kuo YH, Wang CJ, Chen IS. Dihydrobenzo phenanthridine alkaloids from stem bark of Zanthoxylum nitidum. J Nat Prod 2008; 71(4): 669-73.
[] [PMID: 18303853]
Omosa LK, Nchiozem-Ngnitedem VA, Mukavi J, et al. Cytotoxic alkaloids from the root of Zanthoxylum paracanthum (mildbr) Kokwaro. Nat Prod Res 2022; 36(10): 2518-25.
[] [PMID: 33969756]
Liu H, Feng J, Feng K, Lai M. Optimization of the extraction conditions and quantification by RP-LC analysis of three alkaloids in Zanthoxylum nitidum roots. Pharm Biol 2014; 52(2): 255-61.
[] [PMID: 24074362]
Shi Y, Cao T, Sun Y, Xia J, Wang P, Ma J. Nitidine Chloride inhibits cell proliferation and invasion via downregulation of YAP expression in prostate cancer cells. Am J Transl Res 2019; 11(2): 709-20.
[PMID: 30899373]
Fang Z, Tang Y, Jiao W, et al. Nitidine chloride induces apoptosis and inhibits tumor cell proliferation via suppressing ERK signaling pathway in renal cancer. Food Chem Toxicol 2014; 66: 210-6.
[] [PMID: 24508476]
Sun M, Zhang N, Wang X, et al. Hedgehog pathway is involved in nitidine chloride induced inhibition of epithelial-mesenchymal transition and cancer stem cells-like properties in breast cancer cells. Cell Biosci 2016; 6(1): 44.
[] [PMID: 27313840]
Katheder NS, Khezri R, O’Farrell F, et al. Microenvironmental autophagy promotes tumour growth. Nature 2017; 541(7637): 417-20.
[] [PMID: 28077876]
Zuo H, Chen C, Ma L, Min QX, Shen YH. Caspase-8 knockdown suppresses apoptosis, while induces autophagy and chemo-sensitivity in non-small cell lung cancer cells. Am J Transl Res 2020; 12(10): 6478-89.
[PMID: 33194045]
Li YJ, Lei YH, Yao N, et al. Autophagy and multidrug resistance in cancer. Chin J Cancer 2017; 36(1): 52.
[] [PMID: 28646911]
Cordani M, Somoza Á. Targeting autophagy using metallic nanoparticles: a promising strategy for cancer treatment. Cell Mol Life Sci 2019; 76(7): 1215-42.
[] [PMID: 30483817]
Xi G, Wang M, Sun B, et al. Targeting autophagy augments the activity of DHA-E3 to overcome p-gp mediated multi-drug resistance. Biomed Pharmacother 2016; 84: 1610-6.
[] [PMID: 27825801]
Zhou J, Jiang Y, Chen H, Wu Y, Zhang L. Tanshinone I attenuates the malignant biological properties of ovarian cancer by inducing apoptosis and autophagy via the inactivation of PI3K/AKT/mTOR pathway. Cell Prolif 2020; 53(2): e12739.
[] [PMID: 31820522]
Xu Z, Han X, Ou D, et al. Targeting PI3K/AKT/mTOR-mediated autophagy for tumor therapy. Appl Microbiol Biotechnol 2020; 104(2): 575-87.
[] [PMID: 31832711]
Liu B, Deng X, Jiang Q, et al. Scoparone improves hepatic inflammation and autophagy in mice with nonalcoholic steatohepatitis by regulating the ROS/P38/Nrf2 axis and PI3K/AKT/mTOR pathway in macrophages. Biomed Pharmacother 2020; 125: 109895.
[] [PMID: 32000066]

© 2024 Bentham Science Publishers | Privacy Policy