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Quinacrine and Curcumin in combination decreased the breast cancer angiogenesis by modulating ABCG2 via VEGF A

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Journal of Cell Communication and Signaling Aims and scope

Abstract

Cancer stem cells (CSCs) cause drug resistance in cancer due to its extensive drug efflux, DNA repair and self-renewal capability. ATP binding cassette subfamily G member 2 (ABCG2) efflux pump afford protection to CSCs in tumors, shielding them from the adverse effects of chemotherapy. Although the role of ABCG2 in cancer progression, invasiveness, recurrence are known but its role in metastasis and angiogenesis are not clear. Here, using in vitro (CSCs enriched side population [SP] cells), ex vivo (patient derived primary cells), in ovo (fertilized egg embryo) and in vivo (patient derived primary tissue mediated xenograft (PDX)) system, we have systematically studied the role of ABCG2 in angiogenesis and the regulation of the process by Curcumin (Cur) and Quinacrine (QC). Cur + QC inhibited the proliferation, invasion, migration and expression of representative markers of metastasis and angiogenesis. Following hypoxia, ABCG2 enriched cells released angiogenic factor vascular endothelial growth factor A (VEGF A) and induced the angiogenesis via PI3K-Akt-eNOS cascade. Cur + QC inhibited the ABCG2 expression and thus reduced the angiogenesis. Interestingly, overexpression of ABCG2 in SP cells and incubation of purified ABCG2 protein in media induced the angiogenesis but knockdown of ABCG2 decreased the vascularization. In agreement with in vitro results, ex vivo data showed similar phenomena. An induction of vascularization was noticed in PDX mice but reduction of vascularization was also observed after treatment of Cur + QC. Thus, data suggested that in hypoxia, ABCG2 enhances the production of angiogenesis factor VEGF A which in turn induced angiogenesis and Cur + QC inhibited the process by inhibiting ABCG2 in breast cancer.

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Data Availability

Experimental data generated during the current study are available from the corresponding author upon reasonable request.

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Acknowledgements

The authors would like to sincerely thank the Indian Council of Medical Research (ICMR), Government of India, for providing a research fellowship (Reference number: 3/2/2/35/2018/Online Onco Fship/NCD-III) to DN.

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Authors and Affiliations

  1. Cancer Biology Division, KIIT School of Biotechnology, KIIT, Deemed to be University, Campus-11, 751024, Patia, Bhubaneswar, Odisha, India

    Deepika Nayak, Subarno Paul, Chinmay Das, Subhasmita Bhal & Chanakya Nath Kundu

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  1. Deepika Nayak
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  2. Subarno Paul
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  3. Chinmay Das
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  4. Subhasmita Bhal
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  5. Chanakya Nath Kundu
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Contributions

DN performed the majority of the experiments and wrote the initial draft of the manuscript. SP, CD, SB helped in performing some of the experiments and analyzed the data. CNK conceived the scientific idea, designed the experiments, and wrote the final version of the manuscript.

Corresponding author

Correspondence to Chanakya Nath Kundu.

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Ethical Approval and Consent to participate

The mice experiments were carried out according to the guidelines of CPCSEA, New Delhi and approved by the Institutional Animal Ethics Committee (IAEC), KIIT, Deemed to be University (Ethical clearance approval Regd. #1577/PO/Re/S/2011/CPCSEA). The experiments using patient tissue samples were conducted according to the guidelines of the Declaration of Helsinki and approved by the Institutional Ethics Committee of Acharya Harihar Regional Cancer Centre, Cuttack, Odisha, India (Ethical clearance approval Regd. #ECR/297/Inst/OR/2013). The experiments using HUVECs were performed according to the guidelines of the Declaration of Helsinki and approved by the Institutional Ethics Committee of Kalinga Institute of Medical Sciences hospital, Bhubaneswar, Odisha, India (Ethical clearance approval Regd. #KIMS/KIIT/IEC/55/2016).

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Nayak, D., Paul, S., Das, C. et al. Quinacrine and Curcumin in combination decreased the breast cancer angiogenesis by modulating ABCG2 via VEGF A. J. Cell Commun. Signal. 17, 609–626 (2023). https://doi.org/10.1007/s12079-022-00692-0

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