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Journal of Physiology and Biochemistry

, Volume 74, Issue 2, pp 223–234 | Cite as

7,8-Dihydroxycoumarin exerts antitumor potential on DMBA-induced mammary carcinogenesis by inhibiting ERα, PR, EGFR, and IGF1R: involvement of MAPK1/2-JNK1/2-Akt pathway

  • Abhishek Kumar
  • Priyashree Sunita
  • Shivesh Jha
  • Shakti P. Pattanayak
Original Article

Abstract

Breast cancer (BC) is a persistent and impulsive metabolic disorder with the highest prevalence in women, worldwide. 7,12-Dimethylbenz(a)anthracene (DMBA) is a potent polyaromatic hydrocarbon (PAH)-based carcinogen producing mammary carcinomas in rats resembling the human hormone-dependent BC. 7,8-Dihydroxycoumarin (78DC) is a coumarin derivative that possesses diversified and favorable pharmacology profile to be considered in anticancer research against various malignancies. The present study was intended to investigate the antiproliferative and chemotherapeutic potentials of 78DC (20, 40, and 80 mg/kg BW) against DMBA (20 mg in olive oil)-induced mammary carcinoma Sprague-Dawley rats. We established the in silico approach for evaluation of the effect of 78DC on hormonal (estrogen receptor-α (ERα), progesterone receptor (PR)), growth factor receptors (EGFR and IGFR), 17β-hydroxysteroid dehydrogenase type 1 (17β-HD1), and aromatase. Effect of 78DC on estrogen synthesis, tumor growth, proliferation markers (Ki-67 and PCNA), cytokines (IL-10, IL-1β, IL-12), chemokine (MCP-1), and cellular expressions of ERα, PR, EGFR, IGF1R, p-MAPK1/2, p-JNK1/2, p-Akt, 17β-HD1, and aromatase was evaluated in mammary carcinoma bearing SD rats. DMBA induces large tumor burden and histological alterations in mammary gland with a subsequent increase in ERα, PR, EGFR, IGF1R, Ki-67, proliferating cell nuclear antigen (PCNA ), cytokines, and chemokine expressions. This was also correlated with the changes in rapid cell differentiation and proliferation. In contrast, 78DC treatment to the cancer-bearing animals abbreviated these changes and revealed to possess antitumorigenic and antiproliferative potentials. Further, a significant decrease in expressions of ERα, PR, EGFR, IGFR, p-MAPK1/2, p-JNK1/2, p-Akt, 17β-HD1, and aromatase signifies a reduction in estrogen sensitivity and secondary signaling pathways that may contribute to the prevention of tumor growth. The current findings revealed that 78DC potentially reduce cancer cell proliferation and reverted mammary cancer-induced changes in experimental animals in a dose-dependent manner.

Keywords

DMBA 7,8-Dihydroxycoumarin Proliferation markers ERα PR EGFR IGF1R Signaling pathway 

Notes

Acknowledgements

Authors need to express thanks to University Grants Commission for the RGNF support (F1-17.1/2013-14/RGNF-2013-14-SC-CHH-46132). The authors are greatly acknowledging the authorities of the organizations of SP Pattanayak, A Kumar, and S Jha for the necessary infrastructure and facilities provided for the smooth running of the project.

Compliance with ethical standards

The study protocol was approved by IAEC (Institutional Animal Ethics Committee; Protocol Approval No. BIT/PH/IAEC/24/2013).

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

13105_2018_608_MOESM1_ESM.pptx (2.7 mb)
ESM 1 (PPTX 2749 kb)

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Copyright information

© University of Navarra 2018

Authors and Affiliations

  • Abhishek Kumar
    • 1
  • Priyashree Sunita
    • 2
  • Shivesh Jha
    • 3
  • Shakti P. Pattanayak
    • 1
  1. 1.Division of Pharmacology, Department of Pharm. Sciences & TechnologyBirla Institute of TechnologyRanchiIndia
  2. 2.Government Pharmacy Institute, Department of Health, Family Welfare and Medical EducationGovernment of JharkhandRanchiIndia
  3. 3.Division of Pharmacognosy, Department of Pharmaceutical Sciences & TechnologyBirla Institute of TechnologyRanchiIndia

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