Abstract
Adipose-derived stem cells (ADSCs) primed with paclitaxel (PTX) are now hypothesized to represent a potential Trojan horse to vehicle and deliver PTX into tumors. We analyzed the anticancer activity of PTX released by ADSCs primed with PTX (PTX-ADSCs) (~20 ng/mL) in a panel of ovarian cancer (OvCa) cells sensitive or resistant to PTX. We used two (2D) and three dimensional (3D) in vitro models (multicellular tumor spheroids, MCTSs, and heterospheroids) to mimic tumor growth in ascites. The coculture of OvCa cells with PTX-ADSCs inhibited cell viability in 2D models and in 3D heterospheroids (SKOV3-MCTSs plus PTX-ADSCs) and counteracted PTX-resistance in Kuramochi cells. The cytotoxic effects of free PTX and of equivalent amounts of PTX secreted in PTX-ADSC-conditioned medium (CM) were compared. PTX-ADSC-CM decreased OvCa cell proliferation, was more active than free PTX and counteracted PTX-resistance in Kuramochi cells (6.0-fold decrease in the IC50 values). Cells cultivated as 3D aggregated MCTSs were more resistant to PTX than 2D cultivation. PTX-ADSC-CM (equivalent-PTX) was more active than PTX in MCTSs and counteracted PTX-resistance in all cell lines. PTX-ADSC-CM also inhibited OvCa-MCTS dissemination on collagen-coated wells. In conclusion, PTX-ADSCs and PTX-MSCs-CM may represent a new option with which to overcome PTX-resistance in OvCa.
Highlights
Improving the delivery of cancer therapies to tumor sites is fundamental to decreasing their negative side effects
Ovarian cancer cell lines A2780 and A2780cis were from Sigma-Aldrich; SKOV3 (HTB-77) and COV318 were obtained from the American Type Culture Collection (ATCC); OVCAR5 (NIH) cells were provided by Dr Baldassarre (CRO, Aviano, Italy); Kuramochi cells (JCRB0098), resistant to paclitaxel [15], were from JCRB Cell Bank; and OVCAR8 cells were from the National Cancer Institute Developmental Therapeutics Program Tumor Repository
Since multicellular tumor spheroids (MCTSs) and heterospheroids mimic tumor growth in ascitic fluid and are considered effective first-line approaches to study in vitro drug activity, we used both cellular models to evaluate the anticancer effects of Adipose-derived stem cells (ADSCs) primed with PTX (PTX-ADSCs)
Summary
Improving the delivery of cancer therapies to tumor sites is fundamental to decreasing their negative side effects. In this context, mesenchymal stem cells (MSCs) have been proposed as cellular vehicles for targeted cancer therapies, thanks to their tumor homing properties. MSCs are present in many different mammalian tissues (adipose tissue, bone marrow, skin, umbilical cord blood, placenta, etc.) and are easy to isolate and expand [1]. Based on these characteristics, several laboratories set up models of engineered MSCs as vehicles for anticancer molecules, such as interferons, growth factors, chemokines and drugs [2,3]. EVs can carry lipophilic and hydrophilic drugs, representing an additional manner for anticancer drug delivery [9,11]
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