The synergistic effect of resveratrol and curcumin on oncogenic lncRNA MAPT-IT1 and ferroptosis-related genes in breast cancer.

Breast cancer remains a critical global health issue, necessitating the development of novel therapeutic strategies. Long non-coding RNAs (lncRNAs), such as MAPT-IT1, have emerged as key regulators of cancer progression. Meanwhile, ferroptosis, a form of iron-dependent programmed cell death, has gained attention as a promising target for anticancer therapies. Additionally, autophagy, a cellular process responsible for recycling damaged components, is increasingly recognized for its dual role in promoting cancer cell survival and contributing to resistance against treatments. This study explores the combined therapeutic potential of resveratrol and curcumin, two naturally occurring compounds, in targeting breast cancer cells. Specifically, we examine how these agents interact with MAPT-IT1 expression and ferroptosis-related genes, aiming to uncover a synergistic strategy to enhance treatment efficacy. MDA-MB-231 and MCF7 breast cancer cells, together with normal human foreskin fibroblasts (HFF2), were exposed to resveratrol, curcumin, or their combination at a fixed 5:1.5 ratio (resveratrol:curcumin). Cell viability was measured using the MTT assay, and IC₅₀ values as well as synergistic interactions were determined using CompuSyn software. To pinpoint dysregulated lncRNAs, TCGA-BRCA RNA-Seq datasets were analyzed in silico, with MAPT-IT1 emerging as a top candidate. Following treatment, quantitative real-time PCR was performed to quantify changes in MAPT-IT1 expression and in genes associated with autophagy and ferroptosis. Resveratrol and curcumin decreased the viability of breast cancer cells, with curcumin exhibiting markedly greater potency (IC₅₀ = 12.60 µM) compared to resveratrol (IC₅₀ = 134.10 µM). When combined, they acted synergistically (combination index = 0.943), reducing the overall IC₅₀ to 39.18 µM. Computational analyses further demonstrated that MAPT-IT1 is overexpressed in breast tumors and correlates with worse patient survival (p = 0.032). Treatment-most notably the combined regimen-significantly suppressed MAPT-IT1 levels by up to sixfold in MDA-MB-231 cells (p < 0.0001). Additionally, the dual treatment modulated MAPT-IT1 alongside genes governing autophagy and ferroptosis, suggesting activation of both cell death pathways. Resveratrol and curcumin work together to inhibit breast cancer cell proliferation by reducing levels of the oncogenic lncRNA MAPT-IT1 and activating autophagy and ferroptosis pathways. This natural compound duo represents a compelling therapeutic strategy for breast cancer and merits additional clinical investigation.