Plant-Based α-Linolenic Acid as a Superior Nutraceutical to Modulates Apoptosis, Hypoxic Signaling, and Lipid Metabolic Pathway in Breast Cancer: A Comparative Preclinical Study.

In this study, we investigated and compared the anticarcinogenic efficacy of plant-derived α-linolenic acid (P-ALA) and marine-derived α-linolenic acid (M-ALA) using MCF-7 breast cancer cell line and mammary gland carcinoma model induced by N-methyl-N-nitrosourea (MNU). In vitro MTT assessment on ER+ MCF-7 cells exhibited significant cell viability with P-ALA (IC505.57 µM) when compared with M-ALA (IC505.91 µM) and tamoxifen (TAM) (IC50 9.16 µM). Mitochondrial-mediated apoptosis with apoptotic changes were more evident after P-ALA treatment when scrutinized using DAPI, JC-1, and AO/EtBr staining. The P-ALA (p > 0.001***) and M-ALA (p > 0.001***) reversed the cachexia associated with MNU and positively restored lipid profiles (↓TG, ↓LDL, ↓VLDL, and ↑HDL) (p > 0.001***). ECG and HRV analysis showed that P-ALA-HD effectively restored autonomic functions. Lactate analysis P-ALA-HD significantly reduced lactate accumulation. Immunoblotting indicated upregulation of pro-apoptotic (BAX; BAD and caspase-3 at p > 0.001***) and down-regulation of Bcl-2 (p > 0.001***). P-ALA also inhibited lipogenesis (↓SREBP-1c and FASN↑; p > 0.001***), glucose and lactate transport (GLUT-1↓, MCT-1 ↓, and MCT-4↓ at p > 0.001***), hypoxic signaling (↓HIF-1α p > 0.001*** and ↑PHD2 p > 0.001***), and intrinsic mitochondrial apoptotic marker (VDAC-1↓p > 0.001***). P-ALA demonstrated anticancer, lipid-modulating, and cardioprotective that underscore the potential of P-ALA as efficacious and sustainable therapeutic approach for management of breast cancer.