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Effects of increased accumulation of doxorubicin due to emodin on efflux transporter and LRP1 expression in lung adenocarcinoma and colorectal carcinoma cells

  • Vidhya V. Iyer
  • P. Yoga Priya
  • Jeipreeti Kangeyavelu
Article
  • 61 Downloads

Abstract

Treatment with doxorubicin (dox) and emodin, separately and together, under normoxic and hypoxia-like conditions induced by CoCl2, led to greater intracellular compound accumulation over 10 h post-addition in the presence of CoCl2 in lung adenocarcinoma (A549) and colorectal carcinoma (HCT-15) cell lines. Confocal microscopy revealed that emodin, by itself, showed high cytosolic distribution in both cell lines, at 40 min post-addition but had entered the nuclei by 2 h, while dox entered the nuclei by 40 min. Both compounds modulated the expression of the efflux transporters (PgP, ABCG2, or MRP1-4) and the endocytic receptor, low-density lipoprotein receptor-related protein 1 (LRP1), to different extents under the study conditions. Efflux transporter upregulation was linked to lower intracellular compound levels due to greater efflux. Increased dox accumulation was accompanied by unaltered expression or upregulation of LRP1 in A549 cells. In both cell lines, increased accumulation of dox and emodin was observed whenever LRP1 and the efflux transporters known to transport dox and emodin were all up- or downregulated concomitantly. Increased growth inhibition was linked to co-treatment with dox and emodin and with increased ligand accumulation. The results presented in this study raise the hypothesis that higher production of LRP1 protein may be associated with higher endocytosis of upregulated transporter proteins at the cell surface, and hence, increased dox and emodin accumulation and growth inhibition. If so, elevation of LRP1 expression may be a useful target for interventions to promote the efficacy of these and other anticancer drugs.

Keywords

Accumulation Cancer Doxorubicin Efflux transporter Emodin LRP1 

Notes

Acknowledgements

The authors thank Dr. K.G. Thirumurugaan (Translational Research Platform for Veterinary Biologicals, Tamil Nadu Veterinary and Animal Sciences University) for his support in confocal microscopy. We are also grateful to Ms. Kavitha Murugan for her help with the revision of figures. This study and YP (as Junior Research Fellow) were supported financially through SB/YS/LS-138/2013 from Science Engineering and Research Board (SERB), Government of India.

Author contributions

Conceived and designed the experiments: VI; performed the experiments: JK (GI, qPCR), YP (accumulation, qPCR); analyzed the data: VI, JK, YP; wrote the paper: VI.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest in this study.

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.School of Biosciences and TechnologyVellore Institute of TechnologyVelloreIndia
  2. 2.Department of Chemical EngineeringIndian Institute of Technology Bombay PowaiMumbaiIndia
  3. 3.MaduraiIndia
  4. 4.ChennaiIndia

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