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Piperlongumine, a piper alkaloid, enhances the efficacy of doxorubicin in breast cancer: involvement of glucose import, ROS, NF-κB and lncRNAs

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Abstract

Piperlongumine (PL, piplartine) is an alkaloid derived from the Piper longum L. (long pepper) roots. Originally discovered in 1961, the biological activities of this molecule against some cancer types was reported during the last decade. Whether PL can synergize with doxorubicin and the underlying mechanism in breast cancer remains elusive. Herein, we report the activities of PL in numerous breast cancer cell lines. PL reduced the migration and colony formation by cancer cells. An enhancement in the sub-G1 population, reduction in the mitochondrial membrane potential, chromatin condensation, DNA laddering and suppression in the cell survival proteins was observed by the alkaloid. Further, PL induced ROS generation in breast cancer cells. While TNF-α induced p65 nuclear translocation, PL suppressed the translocation in cancer cells. The expression of lncRNAs such as MEG3, GAS5 and H19 were also modulated by the alkaloid. The molecular docking studies revealed that PL can interact with both p65 and p50 subunits. PL reduced the glucose import and altered the pH of the medium towards the alkaline side. PL also suppressed the expression of glucose and lactate transporter in breast cancer cells. In tumor bearing mouse model, PL was found to synergize with doxorubicin and reduced the size, volume and weight of the tumor. Overall, the effects of doxorubicin in cancer cells are enhanced by PL. The modulation of glucose import, NF-κB activation and lncRNAs expression may have contributory role for the activities of PL in breast cancer.

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Acknowledgements

The study was supported in part from Indian Council of Medical Research, New Delhi (5/13/51/2020/NCD-III) and Science and Engineering Research Board, New Delhi (ECR/2016/000034). NA (5/3/8/40/ITR-F/2019-ITR), VR (3/2/2/43/2018/Online Onco Fship/NCD-III), and SM (3/1/3/JRF-2016/LS/HRD-65-80388) received fellowship from Indian Council of Medical Research, New Delhi. SSV was supported from DBT New Delhi (DBT/2017/BHU/786). AS was supported from UGC New Delhi [No.F.82-1/2018(SA-III)]. We thankfully acknowledge the support from Dr. Rahul K. Singh, Department of Zoology, BHU and Dr. P.K. Nayak, Department of Pharmaceutics Engineering and Technology, IIT BHU with Chemi-Doc system and animal house facility, respectively. The analyses with real-time PCR system and flow cytometer were performed at BHU’s Interdisciplinary School of Life Sciences.

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  1. Anupam Dhasmana

    Present address: Department of Immunology and Microbiology, School of Medicine, University of Texas Rio Grande Valley, Edinburg, TX, USA

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  1. Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi, 221 005, India

    Nikee Awasthee, Anusmita Shekher, Vipin Rai, Sumit S. Verma, Shruti Mishra & Subash C. Gupta

  2. Department of Bioscience and Cancer Research Institute, Himalayan Institute of Medical Sciences, Swami Rama Himalayan University, Dehradun, 248 016, India

    Anupam Dhasmana

  3. Department of Biochemistry, All India Institute of Medical Sciences, Guwahati, India

    Subash C. Gupta

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Awasthee, N., Shekher, A., Rai, V. et al. Piperlongumine, a piper alkaloid, enhances the efficacy of doxorubicin in breast cancer: involvement of glucose import, ROS, NF-κB and lncRNAs. Apoptosis 27, 261–282 (2022). https://doi.org/10.1007/s10495-022-01711-6

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