The Secretome of Human Neonatal Mesenchymal Stem Cells Modulates Doxorubicin-Induced Cytotoxicity: Impact in Non-Tumor Cells

Abstract

Doxorubicin (Dox) is one of the most widely used treatments for breast cancer, although limited by the well-documented cardiotoxicity and other off-target effects. Mesenchymal stem cell (MSC) secretome has shown immunomodulatory and regenerative properties, further potentiated under 3D conditions. This work aimed to uncover the effect of the MSC-derived secretome from 3D (CM3D) or 2D (CM2D) cultures, in human malignant breast cells (MDA-MB-231), non-tumor breast epithelial cells (MCF10A) and differentiated AC16 cardiomyocytes, co-treated with Dox. A comprehensive proteomic analysis of CM3D/CM2D was also performed to unravel the underlying mechanism. CM3D/CM2D co-incubation with Dox revealed no significant differences in MDA-MB-231 viability when compared to Dox alone, whereas MCF10A and AC16 viability was consistently improved in Dox+CM3D-treated cells. Moreover, neither CM2D nor CM3D affected Dox anti-migratory and anti-invasive effects in MDA-MB-231. Notably, Ge-LC-MS/MS proteomic analysis revealed that CM3D displayed protective features that might be linked to the regulation of cell proliferation (CAPN1, CST1, LAMC2, RANBP3), migration (CCN3, MMP8, PDCD5), invasion (TIMP1/2), oxidative stress (COX6B1, AIFM1, CD9, GSR) and inflammation (CCN3, ANXA5, CDH13, GDF15). Overall, CM3D decreased Dox-induced cytotoxicity in non-tumor cells, without compromising Dox chemotherapeutic profile in malignant cells, suggesting its potential use as a chemotherapy adjuvant to reduce off-target side effects.

Exosomal miR-132-3p from mesenchymal stromal cells improves synaptic dysfunction and cognitive decline in vascular dementia

“…Taken together, miR-132-3p promotes the therapeutic effects of MSC EX on neuron impairment of VD. Beside exosomes, there is evidence demonstrated that MSC secretome exerted an important role in regulating target cell functions, such as senescence [37], proliferation [20], and migration [38]. Recent studies also confirmed the protective effects of MSC secretome in neural function [39,40].…”

Exploring the Three-Dimensional Frontier: Advancements in MSC Spheroids and Their Implications for Breast Cancer and Personalized Regenerative Therapies

“…The Dox-related cytotoxic impact persisted in MDA-MB-231 cells. Additionally, CM3D regularly outperformed CM2D, and numerous proteins were shown to be associated with these divergent outcomes [57]. This work envisioned a safer and more effective use of chemotherapeutic medicines while also advancing the development of innovative adjuvant anticancer therapy.…”

“…The most recent investigation, published by Serras et al, sought to comprehend how therapeutically relevant dosages of Dox in conjunction with the secretomes of MSCs affect both tumor and non-tumor cells. Novel methods are required in order to clarify the use of CM from 2D and 3D MSC cultures in both cancer and normal-type cells [57]. In this regard, the current study sought to further clarify the putative underlying mechanisms through a thorough mechanistic proteomic analysis, aiming to assess the effects of the secretomes of MSCs in human malignant breast cells and non-tumor cells (i.e., normal breast epithelial cells and cardiomyocytes) upon co-treatment with Dox.…”