Abstract
The multidrug resistance phenotype is a global phenomenon and causes chemotherapy failure in various cancers, such as in uterine sarcomas that have a high mortality rate. To overcome this phenotype, there is growing research interest in developing new treatment strategies. In this study, we highlight the potential of two essential oils from the Apiaceae family, Pituranthos chloranthus (PC) and Teucrium ramosissimum Desf. (TR), to act as chemopreventive and chemosensitizing agents against two uterine sarcoma cell lines, MES-SA and P-gp-overexpressing MES-SA/Dx5 cells. We found that PC and TR were able to inhibit the cell viability of sensitive MES-SA and resistant MES-SA/Dx5 cells by a slight modulation of the cell cycle and its regulators, but also through a significant induction of apoptosis. The molecular mechanism involved both caspase pathways associated with an overproduction of reactive oxygen species (ROS) and mitochondrial membrane depolarization. Very interestingly, the combination of doxorubicin with PC or TR induced a synergism to increase cell death in resistant MES-SA/Dx5 cells and, subsequently, had the benefit of decreasing the resistance index to doxorubicin. These synergistic effects were reinforced by a decrease in P-gp expression and its P-gp adenosine triphosphatase (ATPase) activity, which subsequently led to intracellular doxorubicin accumulation in resistant sarcoma cells.
Highlights
The majority of research on resistance to chemotherapy drugs has focused on intrinsic and acquired resistance mechanisms of tumor cells [1]
To determine whether essential oils from Apiaceae, Pituranthos chloranthus (PC), and Teucrium ramosissimum Desf. (TR) present potential chemopreventive or chemosensitivity properties against uterine sarcoma, we first evaluated their cytotoxic effects on two well-known human uterine sarcoma cell lines, MES-SA and MES-SA/Dx5
MES-SA/Dx5 was obtained by long-term exposure of MES-SA cells to Dox [29,30] and overexpression of P-gp protein, conferring the multidrug resistance (MDR) phenotype, which is reversed by stable sequence-specific MDR-1 gene silencing [31]
Summary
The majority of research on resistance to chemotherapy drugs has focused on intrinsic and acquired resistance mechanisms of tumor cells [1]. Among the ATP-binding cassette (ABC) transporter superfamily, multidrug resistance proteins (MRPs), breast cancer resistance protein (BCRP/ATP Binding Cassette Subfamily G Member 2 (ABCG2)), and P-glycoprotein (P-gp/MDR1/ATP Binding Cassette Subfamily B Member 1 (ABCB1)), as ATP-driven efflux pumps, characterize classic MDR in cancer cells [3]. These efflux proteins are involved in the resistance to a wide variety of anticancer drugs (vinca-alkaloids, anthracyclines, taxanes, kinase inhibitors, etc.), with a possibility of cross-resistance to these drugs conferred by an overexpression of one ABC transporter [8]. This overexpression can result either from an inherent or acquired process: the former characterizes many cancers, especially colon cancer, which already significantly overexpresses the efflux transporters, and the latter involves a first chemotherapy inducing the overexpression of these carriers and resulting in ineffective chemotherapy [9,10]
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