Multifunctional nanocomposites DDMplusAF inhibit the proliferation and enhance the radiotherapy of breast cancer cells via modulating tumor-promoting factors and metabolic reprogramming

Abstract

Background: Tumor-promoting factors (TPF) and metabolic reprogramming are hallmarks of cancer cell growth. This study is designed to combine the newly synthesized two nanocomposites DDM (HA-FA-2DG@DCA@MgO) and AF (HA-FA-Amygdaline@Fe2O3) with fractionated doses of radiotherapy (6 Gy-FDR; fractionated dose radiotherapy) to improve the efficiency of chemo-radiotherapy against breast cancer cell lines (BCCs; MCF-7 and MDA-MB-231). The physicochemical properties of each nanocomposite were confirmed using energy dispersive XRD, FTIR, HR-TEM, and SEM. The stability of DDMPlusAF was also examined, as well as its release and selective cellular uptake in response to acidic pH. A multiple-MTT assay was performed to evaluate the radiosensitivity of BCCs to DDMPlusAF at 3 Gy (single dose radiotherapy; SDR) and 6 Gy-FDR after 24, 48, and 72 h. Finally, the anti-cancer activity of DDMPlusAF with 6 Gy-FDR was investigated via assessing the cell cycle distribution and cell apoptosis by flow cytometry, the biochemical mediators (HIF-1α, TNF-α, IL-10, P53, PPAR-α, and PRMT-1), along with glycolytic pathway (glucose, HK, PDH, lactate, and ATP) as well as the signaling effectors (protein expression of AKT, AMPK, SIRT-1, TGF-β, PGC-1α, and gene expression of ERR-α) were determined in this study. Results: The stability of DDMPlusAF was verified over 6 days without nanoparticle aggregation. DDMPlusAF release and selectivity data revealed that their release was amenable to the acidic pH of the cancer environment, and their selectivity was enhanced towards BCCs owing to CD44 and FR-α receptors-mediated uptake. After 24 h, DDMPlusAF boosted the BCC radiosensitivity to 6 Gy-FDR. Cell cycle arrest (G2/M and pre-G1), apoptosis induction, modulation of TPF mediators and signaling effectors, and suppression of aerobic glycolysis, all confirmed DDMPlusAF + 6 Gy’s anti-cancer activity. Conclusions: It could be concluded that DDMPlusAF exerted a selective cancer radiosensitizing efficacy with targeted properties for TPF and metabolic reprogramming in BCCs therapy.