, Volume 24, Issue 5–6, pp 414–433 | Cite as

Autophagy inhibition with chloroquine reverts paclitaxel resistance and attenuates metastatic potential in human nonsmall lung adenocarcinoma A549 cells via ROS mediated modulation of β-catenin pathway

  • Satabdi Datta
  • Diptiman Choudhury
  • Amlan Das
  • Dipanwita Das Mukherjee
  • Moumita Dasgupta
  • Shreya Bandopadhyay
  • Gopal ChakrabartiEmail author


Paclitaxel is one of the most commonly used drugs for the treatment of nonsmall cell lung cancer (NSCLC). However acquired resistance to paclitaxel, epithelial to mesenchymal transition and cancer stem cell formation are the major obstacles for successful chemotherapy with this drug. Some of the major reasons behind chemoresistance development include increased ability of the cancer cells to survive under stress conditions by autophagy, increased expression of drug efflux pumps, tubulin mutations etc. In this study we found that inhibition of autophagy with chloroquine prevented development of paclitaxel resistance in A549 cells with time and potentiated the effect of paclitaxel by increased accumulation of superoxide-producing damaged mitochondria, with elevated ROS generation, it also increased the apoptotic rate and sub G0/ G1 phase arrest with time in A549 cells treated with paclitaxel and attenuated the metastatic potential and cancer stem cell population of the paclitaxel-resistant cells by ROS mediated modulation of the Wnt/β-catenin signaling pathway, thereby increasing paclitaxel sensitivity. ROS here played a crucial role in modulating Akt activity when autophagy process was hindered by chloroquine, excessive ROS accumulation in the cell inhibited Akt activity. In addition, chloroquine pre-treatment followed by taxol (10 nM) treatment did not show significant toxicity towards non-carcinomas WI38 cells (lung fibroblast cells). Thus autophagy inhibition by CQ pre-treatment can be used as a fruitful strategy to combat the phenomenon of paclitaxel resistance development as well as metastasis in lung cancer.


Paclitaxel-resistance Chloroquine Autophagy ROS EMT β-Catenin 



Non small cell lung cancer


Reactive oxygen species




Multidrug resistant protein 1


Multidrug resistance-associated protein 1




Epithelial to mesenchymal transition


Reactive oxygen species




Dulbecco’s modified eagle’s Media


Dimethyl sulfoxide


Monodancyl cadaverine


Mitosox red


Oxygen consumption rate


Extracellular acidification rate




Cancer stem cell





The authors wish to thank Dr. Sib Sankar Roy, CSIR – Indian Institute of Chemical Biology, Kolkata, India for helping the use of Seahorse XFe24 Extracellular Flux Analyser facility. The work was supported by grants from Department of Science and Technology, Govt. of India (No. SR/SO/BB-14/2008) and Department of Biotechnology, Government of India (No. BT/ PR12889/AGR/36/624/2009) to G.Chakbarati. FACS and fluorescence microscope instruments facility were developed by grants from National Common Minimum Project, Government. of India. Confocal microscope instrument facility was developed by grants from DBT-IPLS facility. S Datta and D Das Mukherjee were supported by Senior Research fellowship from Council of Scientific and industrial research (CSIR), Government. of India. S. Bandopadhyay is supported by Junior research fellowship from Council of Scientific and industrial research (CSIR), India.

Compliance with Ethical Standards

Conflict of interest

All authors declare that they have no conflicts of interests.

Supplementary material

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Satabdi Datta
    • 1
  • Diptiman Choudhury
    • 2
  • Amlan Das
    • 3
  • Dipanwita Das Mukherjee
    • 1
  • Moumita Dasgupta
    • 1
  • Shreya Bandopadhyay
    • 4
  • Gopal Chakrabarti
    • 1
    Email author
  1. 1.Department of Biotechnology and Dr. B. C. Guha Centre for Genetic Engineering and BiotechnologyUniversity of CalcuttaKolkataIndia
  2. 2.School of Chemistry and BiochemistryThapar Institute of Engineering and TechnologyPatialaIndia
  3. 3.Department of ChemistryNational Institute of TechnologyRavanglaIndia
  4. 4.Cell Biology & Physiology DivisionCSIR – Indian Institute of Chemical BiologyKolkataIndia

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