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Maslinic acid differentially exploits the MAPK pathway in estrogen-positive and triple-negative breast cancer to induce mitochondrion-mediated, caspase-independent apoptosis

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Abstract

Breast cancer accounts for 1.4 million new cases every year. Triple-negative breast cancer (TNBC) is one the leading cause of mortality in developing countries and is associated with early age onset (under 40 years old). Chemotherapy has a poor success rate in patients with TNBC as compared to other types of breast cancers. It is due to the lack of expression of three validated molecular markers for breast cancer, the estrogen and progesterone receptors, and the amplification of HER-2/Neu. Therefore, a clear need exists for a greater understanding of TNBC at all levels and for the development of better therapies. We have studied the anti-tumor effects of a potential drug, maslinic acid, which can be extracted from olive oil industry waste. This natural product showed inhibitory effect at concentrations ranging from 30 to 50 µM within 24 h. It exhibited divergent effects in cell cycle progression for the MCF7 (estrogen positive) cell line when compared with TNBCs like MDA-MB-231 and MDA-MB-468. Also, maslinic acid treatment altered the mitochondrial membrane electrochemical potential and the reactive oxygen species (ROS) levels to cause a caspase-independent programmed cell death. In silico approaches and immunoblotting suggested the involvement of the MAPK pathway explaining the variability in cell cycle progression along with the apoptotic cell death caused by maslinic acid.

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Acknowledgements

RJ is thankful to Department of Health Research, Ministry of Health & Family Welfare, India for Young Scientist position and the financial support for conducting research. AG is grateful to University Grants Commission, India for the Faculty Recharge Position. RJ & AG is thankful to Jawaharlal Nehru University for usage of computational facility. Authors are also thankful to Dr. Sukriti Goyal for the help in Autodock studies.

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    R. Jain & A. Grover

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RJ & AG conceived and designed the study. RJ carried out the experiments and analysed the results. RJ wrote the manuscript. RJ and AG reviewed the manuscript.

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Jain, R., Grover, A. Maslinic acid differentially exploits the MAPK pathway in estrogen-positive and triple-negative breast cancer to induce mitochondrion-mediated, caspase-independent apoptosis. Apoptosis 25, 817–834 (2020). https://doi.org/10.1007/s10495-020-01636-y

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