The mechanistic role of curcumin and its analogs in NSCLC: An evaluation of cell death in preclinical studies

Abstract

Lung cancer is the leading malignancy among males and ranks the second in females, with an estimated two million new diagnoses annually. It ranks the first in cancer-related deaths among men and the second, following breast cancer, among women. The most significant risk factor for lung cancer is smoking. There are two main types of lung cancer: non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), with about 85% of cases falling into the NSCLC category. Even with a combination of treatments for NSCLC, such as surgical intervention, chemotherapy, radiation therapy, and immunotherapy, the 5-year survival rates for those diagnosed with advanced NSCLC have not reached satisfactory levels, with chemotherapy continuing to be the main therapeutic approach. In advanced NSCLC treatment, gemcitabine and platinum-based agents are applied as first-line therapy. However, acquired or pre-existing drug resistance can prevent chemotherapeutic agents from achieving the expected effect on patients and increasing the drug dose can lead to an increase in side effects. In recent years, for these reasons, there has been an increased interest in phytochemicals to enhance the cytotoxic effects of therapeutic agents on cancer cells while minimizing their toxic effects on healthy tissues. One of the most studied phytochemicals is curcumin. Despite its anticancer effects on NSCLC cells, its low stability and poor pharmacokinetics have led to unsatisfactory results in studies. Therefore, a variety of analogs have been synthesized. This review explores the impact of curcumin and its analogs on the pathways of cell death in NSCLC.

Keywords

cell death pathway / curcumin / curcumin analog / non-small cell lung cancer

References

[1] Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024;74(3):229-263.

[2] Inamura K. Lung cancer: understanding its molecular pathology and the 2015 WHO classification. Front Oncol. 2017;7:193.

[3] Baldovini C, Rossi G, Ciarrocchi A. Approaches to tumor classification in pulmonary sarcomatoid carcinoma. Lung Cancer. 2019;10:131-149.

[4] Vassella E, Langsch S, Dettmer MS, et al. Molecular profiling of lung adenosquamous carcinoma: hybrid or genuine type? Oncotarget. 2015;6(27):23905-23916.

[5] Herbst RS, Morgensztern D, Boshoff C. The biology and management of non-small cell lung cancer. Nature. 2018;553(7689):446-454.

[6] Malhotra J, Malvezzi M, Negri E, La Vecchia C, Boffetta P. Risk factors for lung cancer worldwide. Eur Respir J. 2016;48(3):889-902.

[7] Zhu L, Chen R, Yang Q, Liu H, Zheng Q, Li L. Modelling an evaluation of the efficacy and safety of gemcitabine combined with platinum in the treatment of non-small cell lung cancer. J Clin Pharm Ther. 2022;47(7):986-994.

[8] Ettinger DS, Wood DE, Aggarwal C, et al. NCCN guidelines insights: non-small cell lung cancer, version 1.2020. J Natl Compr Cancer Netw. 2019;17(12):1464-1472.

[9] Anand P, Sundaram C, Jhurani S, Kunnumakkara AB, Aggarwal BB. Curcumin and cancer: an “old-age” disease with an “age-old” solution. Cancer Lett. 2008;267(1):133-164.

[10] Nagahama K, Utsumi T, Kumano T, Maekawa S, Oyama N, Kawakami J. Discovery of a new function of curcumin which enhances its anticancer therapeutic potency. Sci Rep. 2016;6:30962.

[11] Xia YQ, Wei XY, Li WL, et al. Curcumin analogue A501 induces G2/M arrest and apoptosis in non-small cell lung cancer cells. Asian Pac J Cancer Prev. 2014;15(16):6893-6898.

[12] Wu L, Xu G, Li N, Zhu L, Shao G. Curcumin analog, HO-3867, induces both apoptosis and ferroptosis via multiple mechanisms in NSCLC cells with wild-type p53. Evid Based Complement Alternat Med: eCAM. 2023;2023:8378581.

[13] Chang M, Shang M, Yuan F, Guo W, Wang C. EF24 exerts cytotoxicity against NSCLC via inducing ROS accumulation. Cancer Cell Int. 2021;21(1):531.

[14] Dai X, Zhang J, Guo G, et al. A mono-carbonyl analog of curcumin induces apoptosis in drug-resistant EGFR-mutant lung cancer through the generation of oxidative stress and mitochondrial dysfunction. Cancer Manag Res. 2018;10:3069-3082.

[15] Zhang L, Qiang P, Yu J, et al. Identification of compound CA-5f as a novel late-stage autophagy inhibitor with potent anti-tumor effect against non-small cell lung cancer. Autophagy. 2019;15(3):391-406.

[16] Liu YL, Yang HP, Zhou XD, Gong L, Tang CL, Wang HJ. The hypomethylation agent bisdemethoxycurcumin acts on the WIF-1 promoter, inhibits the canonical Wnt pathway and induces apoptosis in human non-small-cell lung cancer. Curr Cancer Drug Targets. 2011;11(9):1098-1110.

[17] Wan Mohd Tajuddin WNB, Abas F, Othman I, Naidu R. Molecular mechanisms of antiproliferative and apoptosis activity by 1, 5-bis(4-hydroxy-3-methoxyphenyl)1, 4-pentadiene-3-one (MS13) on human non-small cell lung cancer cells. Int J Mol Sci. 2021;22(14):7424.

[18] Zhou GZ, Zhang SN, Zhang L, Sun GC, Chen XB. A synthetic curcumin derivative hydrazinobenzoylcurcumin induces autophagy in A549 lung cancer cells. Pharm Biol. 2014;52(1):111-116.

[19] Zhou GZ, Shi YY, Wei LL, Sun GC. Autophagy induction and antiproliferative effect of a novel curcumin derivative MOMI-1 on the human lung cancer cells A549. J Biochem Mol Toxicol. 2019;33(4):e22280.

[20] Liu H, Zhou BH, Qiu X, et al. T63, a new 4-arylidene curcumin analogue, induces cell cycle arrest and apoptosis through acti-vation of the reactive oxygen species-FOXO3a pathway in lung cancer cells. Free Radical Biol Med. 2012;53(12):2204-2217.

[21] Namwan N, Senawong G, Phaosiri C, et al. HDAC inhibitory and anti-cancer activities of curcumin and curcumin derivative CU17 against human lung cancer A549 cells. Molecules. 2022;27(13):4014.

[22] Wei T, Zheng Z, Wei X, et al. Rational design, synthesis, and pharmacological characterisation of dicarbonyl curcuminoid analogues with improved stability against lung cancer via ROS and ER stress mediated cell apoptosis and pyroptosis. J Enzyme Inhib Med Chem. 2022;37(1):2357-2369.

[23] Liu X, Cui H, Li M, et al. Tumor killing by a dietary curcumin mono-carbonyl analog that works as a selective ROS generator via TrxR inhibition. Eur J Med Chem. 2023;250:115191.

[24] Ye H, Wei X, Wang Z, et al. A novel double carbonyl analog of curcumin induces the apoptosis of human lung cancer H460 cells via the activation of the endoplasmic reticulum stress signaling pathway. Oncol Rep. 2016;36(3):1640-1648.

[25] Onen HI, Yilmaz A, Alp E, et al. EF24 and RAD001 potentiates the anticancer effect of platinum-based agents in human malignant pleural mesothelioma (MSTO-211H) cells and protects nonmalignant mesothelial (MET-5A) cells. Hum Exp Toxicol. 2015;34(2):117-126.

[26] Wang Z, Liu Z, Qu J, et al. Role of natural products in tumor therapy from basic research and clinical perspectives. Acta Mater Med. 2024;3(2):163-206.

[27] Xu X, Chen D, Ye B, Zhong F, Chen G. Curcumin induces the apoptosis of non-small cell lung cancer cells through a calcium signaling pathway. Int J Mol Med. 2015;35(6):1610-1616.

[28] Wu SH, Hang LW, Yang JS, et al. Curcumin induces apoptosis in human non-small cell lung cancer NCI-H460 cells through ER stress and caspase cascade- and mitochondria-dependent pathways. Anticancer Res. 2010;30(6):2125-2133.

[29] Wang C, Song X, Shang M, et al. Curcumin exerts cytotoxicity dependent on reactive oxygen species accumulation in non-small-cell lung cancer cells. Future Oncol. 2019;15(11):1243-1253.

[30] Sen S, Sharma H, Singh N. Curcumin enhances Vinorelbine mediated apoptosis in NSCLC cells by the mitochondrial pathway. Biochem Biophys Res Commun. 2005;331(4):1245-1252.

[31] Zhang J, Zhang T, Ti X, et al. Curcumin promotes apoptosis in A549/DDP multidrug-resistant human lung adenocarcinoma cells through an miRNA signaling pathway. Biochem Biophys Res Commun. 2010;399(1):1-6.

[32] Zhang W, Bai W, Zhang W. miR-21 suppresses the anticancer activities of curcumin by targeting PTEN gene in human non-small cell lung cancer A549 cells. Clin Transl Oncol. 2014;16(8):708-713.

[33] Ye M, Zhang J, Zhang J, Miao Q, Yao L, Zhang J. Curcumin promotes apoptosis by activating the p53-miR-192-5p/215-XIAP pathway in non-small cell lung cancer. Cancer Lett. 2015;357(1):196-205.

[34] Mizushima N, Komatsu M. Autophagy: renovation of cells and tissues. Cell. 2011;147(4):728-741.

[35] Liu G, Pei F, Yang F, et al. Role of autophagy and apoptosis in non-small-cell lung cancer. Int J Mol Sci. 2017;18(2):367.

[36] Chen P, Huang HP, Wang Y, et al. Curcumin overcome primary gefitinib resistance in non-small-cell lung cancer cells through inducing autophagy-related cell death. J Exp Clin Cancer Res. 2019;38(1):254.

[37] Wang A, Wang J, Zhang S, Zhang H, Xu Z, Li X. Curcumin inhibits the development of non-small cell lung cancer by inhibiting autophagy and apoptosis. Exp Ther Med. 2017;14(5):5075-5080.

[38] Liu F, Gao S, Yang Y, et al. Antitumor activity of curcumin by modulation of apoptosis and autophagy in human lung cancer A549 cells through inhibiting PI3K/Akt/mTOR pathway. Oncol Rep. 2018;39(3):1523-1531.

[39] Stockwell BR. Ferroptosis turns 10: emerging mechanisms, physiological functions, and therapeutic applications. Cell. 2022;185(14):2401-2421.

[40] Zhang Y, Guo R, Li J, Zhu L. Research progress on the occurrence and therapeutic mechanism of ferroptosis in NSCLC. Naunyn Schmiedebergs Arch Pharmacol. 2022;395(1):1-12.

[41] Xia X, Wang X, Cheng Z, et al. The role of pyroptosis in cancer: pro-cancer or pro-“host”? Cell Death Dis. 2019;10(9):650.

[42] Liu X, Xia S, Zhang Z, Wu H, Lieberman J. Channelling inflammation: gasdermins in physiology and disease. Nat Rev Drug Discovery. 2021;20(5):384-405.

[43] Lu X, Guo T, Zhang X. Pyroptosis in cancer: friend or foe? Cancers. 2021;13(14):3620.

[44] Tang X, Ding H, Liang M, et al. Curcumin induces ferroptosis in non-small-cell lung cancer via activating autophagy. Thorac Cancer. 2021;12(8):1219-1230.

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2024 The Author(s). Malignancy Spectrum published by John Wiley & Sons Australia, Ltd on behalf of Higher Education Press.