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.
Highlights
Breast cancer is the most frequently diagnosed cancer and the second-leading cause of cancer death in women [1]
In order to understand if the protein content of Mesenchymal stem cell (MSC) conditioned media (CM) (CM2D and CM3D) could suggest a role and justify or support its use as an adjuvant in breast cancer treatment, a Ge-LC-MS/MS proteomics followed by an Ingenuity Pathway Analysis (IPA) of both CM2D and CM3D was performed
We present an approach for using the secretome of MSCs in the perspective of adjuvant treatment to Dox chemotherapy for breast cancer
Summary
Breast cancer is the most frequently diagnosed cancer and the second-leading cause of cancer death in women [1]. The use of anthracyclines, doxorubicin (Dox) and epirubicin, is established as the first line of treatment in solid tumors such as breast cancer [2], as well as in adjuvant treatment. DNA damage, inhibiting cancer cell proliferation, inducing cell cycle arrest and apoptosis. Dox-induced cardiotoxicity greatly impacts its clinical use, affecting the quality of life of patients and often leading to life-threatening conditions [6,7]. Despite the fact that inhibition of topoisomerase IIβ has been recently described in the heart [3, 5], the most studied mechanisms are oxidative stress and dysfunction of mitochondrial bioenergetics ( via topoisomerase IIβ) [3,7,8,9,10,11]. Dox largely accumulates on cardiac tissue because of its affinity to cardiolipin and a higher sensitivity to oxidative insult [7]
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