Continuous docetaxel (DTX) treatment of non-small cell lung cancer induces development of drug resistance, but the mechanism is poorly understood. In this study we performed metabolomics analysis to characterize the metabolic patterns of sensitive and resistant A549 non-small cell lung cancer cells (A549/DTX cells). We showed that the sensitive and resistant A549 cells exhibited distinct metabolic phenotypes: the resistant cells were characterized by an altered microenvironment of redox homeostasis with reduced glutathione and elevated reactive oxygen species (ROS). DTX induction reprogrammed the metabolic phenotype of the sensitive cells, which acquired a phenotype similar to that of the resistant cells: it reduced cystine influx, inhibited glutathione biosynthesis, increased ROS and decreased glutathione/glutathione disulfide (GSH/GSSG); the genes involved in glutathione biosynthesis were dramatically depressed. Addition of the ROS-inducing agent Rosup (25, 50 μg/mL) significantly increased P-glycoprotein expression and reduced intracellular DTX in the sensitive A549 cells, which ultimately acquired a phenotype similar to that of the resistant cells. Supplementation of cystine (1.0 mM) significantly increased GSH synthesis, rebalanced the redox homeostasis of A549/DTX cells, and reversed DTX-induced upregulation of P-glycoprotein, and it markedly improved the effects of DTX and inhibited the growth of A549/DTX in vitro and in vivo. These results suggest that microenvironmental redox homeostasis plays a key role in the acquired resistance of A549 cancer cells to DTX. The enhancement of GSH synthesis by supplementary cystine is a promising strategy to reverse the resistance of tumor cells and has potential for translation in the clinic.
Subscribe to Journal
Get full journal access for 1 year
only $33.25 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Montero A, Fossella F, Hortobagyi G, Valero V. Docetaxel for treatment of solid tumours: a systematic review of clinical data. Lancet Oncol. 2005;6:229–39.
Fulton B, Spencer CM. Docetaxel. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy in the management of metastatic breast cancer. Drugs. 1996;51:1075–92.
Herbst RS, Morgensztern D, Boshoff C. The biology and management of non-small cell lung cancer. Nature. 2018;553:446–54.
Chang A. Chemotherapy, chemoresistance and the changing treatment landscape for NSCLC. Lung Cancer. 2011;71:3–10.
Kim E. Chemotherapy resistance in lung cancer. Adv Exp Med Biol. 2016;893:189–209.
He XJ, Zhang TR. Alteration in the balance of prosurvival and proapoptotic signalling pathways leads to sequence-dependent synergism between docetaxel and sorafenib in human non-small cell lung cancer cell lines. Cell Biochem Biophys. 2014;68:411–8.
Chen HY, Shien K, Suzawa K, Tsukuda K, Tomida S, Sato H, et al. Elacridar, a third-generation ABCB1 inhibitor, overcomes resistance to docetaxel in non-small cell lung cancer. Oncol Lett. 2017;14:4349–54.
Kong WC, Ling XM, Chen Y, Wu XL, Zhao ZQ, Wang WW, et al. Hesperetin reverses P‑glycoprotein‑mediated cisplatin resistance in DDP‑resistant human lung cancer cells via modulation of the nuclear factor‑κB signaling pathway. Int J Mol Med. 2020;45:1213–24.
Hopper-Borge E, Chen ZS, Shchaveleva I, Belinsky MG, Kruh GD. Analysis of the drug resistance profile of multidrug resistance protein 7 (ABCC10): resistance to docetaxel. Cancer Res. 2004;64:4927–30.
Hanahan D, Weinberg R. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74.
Tomita M, Kami K. Cancer. Systems biology, metabolomics, and cancer metabolism. Science. 2012;336:990.
Hiller K, Metallo M. Profiling metabolic networks to study cancer metabolism. Curr Opin Biotechnol. 2013;24:60–8.
Jain M, Nilsson R, Sharma S, Madhusudhan N, Kitami T, Souza A, et al. Metabolite profiling identifies a key role for glycine in rapid cancer cell proliferation. Science. 2012;336:1040–4.
Schulte M, Fu A, Zhao P, Li J, Geng L, Smith S, et al. Pharmacological blockade of ASCT2-dependent glutamine transport leads to antitumor efficacy in preclinical models. Nat Med. 2018;24:194–202.
Sullivan L, Luengo A, Danai LV, Bush LN, Diehl FF, Hosios AM, et al. Aspartate is an endogenous metabolic limitation for tumour growth. Nat Cell Biol. 2018;20:782–8.
Frezza C. Cancer metabolism: addicted to serine. Nat Chem Biol. 2016;12:389–90.
Pacold ME, Brimacombe KR, Chan SH, Rohde JM, Lewis CA, Swier LJ, et al. A PHGDH inhibitor reveals coordination of serine synthesis and one-carbon unit fate. Nat Chem Biol. 2016;12:452–8.
Cao B, Li MJ, Zha WB, Zhao QJ, Gu RR, Liu LS, et al. Metabolomic approach to evaluating adriamycin pharmacodynamics and resistance in breast cancer cells. Metabolomics. 2013;9:960–73.
Ge C, Cao B, Feng D, Zhou F, Zhang JW, Yang N, et al. The down-regulation of SLC7A11 enhances ROS induced P-gp over-expression and drug resistance in MCF-7 breast cancer cells. Sci Rep. 2017;7:3791.
Feng SQ, Wang GJ, Zhang JW, Xie Y, Sun RB, Fei F, et al. Combined treatment with apatinib and docetaxel in A549 xenograft mice and its cellular pharmacokinetic basis. Acta Pharmacol Sin. 2018;39:1670–80.
Wang WJ, Cai QY, Zhou F, Liu JL, Jin XL, Ni P, et al. Impaired pentose phosphate pathway in the development of 3D MCF-7 cells mediated intracellular redox disturbance and multi-cellular resistance without drug induction. Redox Biol. 2018;15:253–65.
Trygg J, Holmes E, Lundstedt T. Chemometrics in metabonomics. J Proteome Res. 2007;6:469–79.
Bjerrum JT. Metabonomics: analytical techniques and associated chemometrics at a glance. Methods Mol Biol. 2015;1277:1–14.
Xia J, Sinelnikov I, Han B, Wishart D. MetaboAnalyst 3.0–making metabolomics more meaningful. Nucleic Acids Res. 2015;43:W251–7.
Yang XL, Liu Y, Li WN, Li AM, Sun Q. DKK4-knockdown enhances chemosensitivity of A549/DTX cells to docetaxel. Acta Biochim Biophys Sin. 2017;49:899–906.
Gan HT, Chen YQ, Ouyang Q. Sulfasalazine inhibits activation of nuclear factor-kappaB in patients with ulcerative colitis. J Gastroenterol Hepatol. 2005;20:1016–24.
Kim JY, Cho H, Sir J, Kim B, Hur J, Youn S, et al. Sulfasalazine induces haem oxygenase-1 via ROS-dependent Nrf2 signalling, leading to control of neointimal hyperplasia. Cardiovasc Res. 2009;82:550–60.
Abbasi M, Mousavi M, Jamalzehi S, Alimohammadi R, Bezvan M, Mohammadi H, et al. Strategies toward rheumatoid arthritis therapy; the old and the new. J Cell Physiol. 2019;234:10018–31.
This work was supported by the National Natural Science Foundation of China, grant number 81773814, “Double First-Class” University project (CPU2018GF01), Leading Technology Foundation Research Project of Jiangsu province (BK20192005) and Sanming Project of Medicine in Shenzhen (SZSM201801060).
The authors declare no competing interests.
About this article
Cite this article
Li, Sj., Cao, B., Lu, Zy. et al. Cystine supplementation rebalances the redox homeostasis of microenvironment in non-small cell lung cancer cells and reverses their resistance to docetaxel. Acta Pharmacol Sin (2021). https://doi.org/10.1038/s41401-020-00610-3
- non-small cell lung cancer cells
- drug resistance
- redox homeostasis