Generating Paclitaxel-Resistant in Cervical Cancer HeLa Cell Line

Muhammad Hasan Bashari, Fachreza Aryo Damara, Isna Nisrina Hardani, Gita Widya Pradini, Tenny Putri, Eko Fuji Ariyanto


Cervical cancer is one of the most leading causes of women death. Currently, paclitaxel is still one of the main therapeutic regimens for cervical cancer patients. However, some patients developed to be paclitaxel-resistant. Hence, studies to find out the novel strategies to resolve this problem are important. Generating resistant cancer cell lines can be utilized as the potent tool to evaluate the efficacy of any therapeutic agent toward cancer drug-resistant problems. Current studies describing the methods to establish chemoresistance are lacking. Moreover, study in Indonesia conducting chemoresistance in cell line is limited. This study was aimed to elaborate the characteristics of HeLa cells during generation of paclitaxel-resistant cervical cancer cells. The parental HeLa cells were exposed to an escalating concentration of paclitaxel for a long time period. Subsequently, cells were divided into two groups for the evaluation of resistance characteristics. The values of inhibitory concentration 50 (IC50) and inhibitory concentration 90 (IC90) were analyzed using 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) assay. Our data showed that the longer exposing periods of paclitaxel, the higher IC50 and IC90 values of HeLa cells are. IC90 of paclitaxel in HeLa Pac RB was increased from 69 pM, 440 pM, 2,561 pM and 10,337 pM on 0th, 1st, 2nd, 3rd and 4th months, respectively. Interestingly, the resistant cells were recovered to be paclitaxel-sensitive when they were not being continuously exposed to paclitaxel. In addition, the paclitaxel resistant cells become less sensitive against 5-FU but not doxorubicin, cisplatin and etoposide. We were able to generate cervical cancer HeLa paclitaxel-resistant cell line. These cell line could potentially be utilized for further studies in order to understand the molecular mechanisms of drug resistance in cervical cancer and as a tool for cancer drug discovery.

Keywords: cervical cancer, drug resistant cell line, paclitaxel resistant cells, stepwise escalating concentration.

Full Text:



Bi W, Wang Y, Sun G, Zhang, X., Wei, Y., et al., 2014, Paclitaxel-resistant HeLa cells have up-regulated levels of reactive oxygen species and increased expression of taxol resistance gene 1, Pak. J. Pharm. Sci., 27, 871–878.

Demidenko, Z.N., Kalurupalle, S., Hanko, C., Lim, C-u., Broude, E., et al., 2008, Mechanism of G1-like arrest by low concentrations of paclitaxel: next cell cycle p53-dependent arrest with sub G1 DNA content mediated by prolonged mitosis, Oncogene, 27, 4402–4410. CrossRef

Dumontet, C. and Jordan, M.A., 2010, Microtubule-binding agents: a dynamic field of cancer therapeutics, Nat. Rev. Drug Discov., 9, 790–803. CrossRef

de Figueiredo-Pontes, L.L., Pintão, M-C.T., Oliveira, L.C.O., Dalmazzo, L.F.F., Jacomo, R.H., et al., 2008, Determination of P-glycoprotein, MDR-related protein 1, breast cancer resistance protein, and lung-resistance protein expression in leukemic stem cells of acute myeloid leukemia, Cytom. Part B Clin. Cytom., 74(3), 163–168. CrossRef

Kavallaris, M., 2010, Microtubules and resistance to tubulin-binding agents, Nat. Rev. Cancer, 10(3), 194–204. CrossRef

Koh, W-J., Abu-Rustum, N.R., Bean, S., Bradley, K., Campos, S.M., et al., 2019, Cervical Cancer, Version 3.2019, NCCN Clinical Practice Guidelines in Oncology, J. Natl. Compr. Cancer Netw., 17(1), 64–84. CrossRef

Lee, D-k., Kim, Y.H., Kim, J-S. and Seol, W., 2004, Induction and characterization of taxol-resistance phenotypes with a transiently expressed artificial transcriptional activator library, Nucleic Acids Res., 32(14), e116–e116. CrossRef

Lu, H., Forbes, R.A. and Verma, A., 2002, Hypoxia-inducible Factor 1 Activation by Aerobic Glycolysis Implicates the Warburg Effect in Carcinogenesis, J. Biol. Chem., 277(26), 23111–23115. CrossRef

Mansoori, B., Mohammadi, A., Davudian, S., Shirjang, S. and Baradaran, B., 2017, The Different Mechanisms of Cancer Drug Resistance: A Brief Review, Adv. Pharm. Bull., 7(3), 339–348. CrossRef

Mariani, M., Karki, R., Spennato, M., Pandya, D., He, S., et al., 2015, Class III β-tubulin in normal and cancer tissues, Gene, 563(2), 109–114. CrossRef

McDermott, M., Eustace, A.J., Busschots, S., Breen, L., Crown, J., et al., 2014, In vitro Development of Chemotherapy and Targeted Therapy Drug-Resistant Cancer Cell Lines: A Practical Guide with Case Studies, Front. Oncol., 4, 40. CrossRef

McGuire, S., 2016, World Cancer Report 2014. Geneva, Switzerland: World Health Organization, International Agency for Research on Cancer, WHO Press, 2015, Adv. Nutr., 7(2), 418–419. CrossRef

Meerloo, J Van, Kaspers, G.J.L. and Cloos, J., 2011, Cancer Cell Culture, Totowa, NJ: Humana Press. CrossRef

Park, S.Y., Kim, W.J., Byun, J.H., Lee, J.J., Jeoung, D., et al., 2018, Role of DDX53 in taxol-resistance of cervix cancer cells in vitro, Biochem. Biophys. Res. Commun., 506(3), 641–647. CrossRef

Peng, X., Gong, F., Chen, Y., Jiang, Y., Liu, J., et al., 2014, Autophagy promotes paclitaxel resistance of cervical cancer cells: involvement of Warburg effect activated hypoxia-induced factor 1-α-mediated signaling, Cell Death Dis., 5(8), e1367. CrossRef

Shen, Y., Zhou, J., Li, Y., Ye, F., Wan, X., et al., 2014, miR-375 Mediated Acquired Chemo-Resistance in Cervical Cancer by Facilitating EMT, PLoS One, 9(10), e109299. CrossRef

Soca-Chafre, G., Rivera-Orduña, F.N., Hidalgo-Lara, M.E., Hernandez-Rodriguez, C., Marsch, R., et al., 2011, Molecular phylogeny and paclitaxel screening of fungal endophytes from Taxus globosa, Fungal Biol., 115, 143–156. CrossRef

Zhang, H-L., Ruan, L., Zheng, L-M., Whyte, D., Tzeng, C-M., et al., 2012, Association between class III β-tubulin expression and response to paclitaxel/vinorebine-based chemotherapy for non-small cell lung cancer: a meta-analysis, Lung Cancer, 77(1), 9–15. CrossRef

Zhou, M., Li, L., Li, L., Lin, X., Wang, F., et al., 2019, Overcoming chemotherapy resistance via simultaneous drug-efflux circumvention and mitochondrial targeting, Acta Pharm. Sin. B, 9(3), 615–625. CrossRef

Zhu, H., Luo, H., Zhang, W., Shen, Z., Hu, X., et al., 2016, Molecular mechanisms of cisplatin resistance in cervical cancer, Drug Des. Devel. Ther., 10>, 1885–1895. CrossRef

Zou, S-H., Du, X., Lin, H., Wang, P-C., Li, M., 2018, Paclitaxel inhibits the progression of cervical cancer by inhibiting autophagy via lncRNARP11-381N20.2, Eur. Rev. Med. Pharmacol. Sci., 22(10), 3010–3017. CrossRef


Copyright (c) 2020 Muhammad Hasan Bashari, Fachreza Aryo Damara, Isna Nisrina Hardani, Gita Widya Pradini, Tenny Putri, Eko Fuji Ariyanto

Indexed by:





Indonesian Society for Cancer Chemoprevention