Alpha-linolenic acid stabilizes HIF-1 α and downregulates FASN to promote mitochondrial apoptosis for mammary gland chemoprevention
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Subhadeep Roy1, Atul Kumar Rawat2, Shreesh Raj Sammi3, Uma Devi4, Manjari Singh1, Swetlana Gautam1, Rajnish Kumar Yadav1, Jitendra Kumar Rawat1, Lakhveer Singh1, Mohd. Nazam Ansari5, Abdulaziz S. Saeedan5, Rakesh Pandey3, Dinesh Kumar2 and Gaurav Kaithwas1
1Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, Lucknow (UP), India
2Central for Biomedical Research, Sanjay Gandhi Post Graduate Institute of Medical Sciences Campus, Lucknow (UP), India
3Department of Microbial Technology and Nematology, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow (UP), India
4Department of Pharmaceutical Sciences, Faculty of Health and Medical Sciences, Sam Higginbottom Institute of Agricultural Sciences and Technology, Allahabad (UP), India
5Department of Pharmacology, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj, KSA
Gaurav Kaithwas, email: [email protected]
Keywords: alpha linolenic acid, apoptosis, polyunsaturated fatty acid, hypoxia, fatty acid synthase
Received: February 06, 2017 Accepted: June 12, 2017 Published: July 25, 2017
Alpha linolenic acid is an essential polyunsaturated fatty acid and is reported to have the anti-cancer potential with no defined hypothesis or mechanism/s. Henceforth present study was in-quested to validate the effect of alpha linolenic acid on mitochondrial apoptosis, hypoxic microenvironment and de novo fatty acid synthesis using in-vitro and in-vivo studies. The IC50 value of alpha linolenic acid was recorded to be 17.55μM against ER+MCF-7 cells. Treatment with alpha linolenic acid was evident for the presence of early and late apoptotic signals along with mitochondrial depolarization, when studied through acridine orange/ethidium bromide and JC-1 staining. Alpha linolenic acid arrested the cell cycle in G2/M phase. Subsequently, the in-vivo efficacy was examined against 7, 12-dimethylbenz anthracene induced carcinogenesis. Treatment with alpha linolenic acid demarcated significant effect upon the cellular proliferation as evidenced through decreased in alveolar bud count, restoration of the histopathological architecture and loss of tumor micro vessels. Alpha linolenic acid restored the metabolic changes to normal when scrutinized through 1H NMR studies. The immunoblotting and qRT-PCR studies revealed participation of mitochondrial mediated death apoptosis pathway and curtailment of hypoxic microenvironment after treatment with alpha linolenic acid. With all above, it was concluded that alpha linolenic acid mediates mitochondrial apoptosis, curtails hypoxic microenvironment along with inhibition of de novo fatty acid synthesis to impart anticancer effects.
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