Antioxidant α‐mangostin downregulates ATP‐binding cassette transporters in HuT78 cells

Abstract

Sézary syndrome (SS) is an aggressive form of cancer called cutaneous T‐cell lymphoma (CTCL). Patients with SS carry poor prognosis, with a median survival of approximately 40 months after diagnosis and a 5‐year survival rate below 40%. The offending neoplastic T cells for SS known as Sézary cells are aggressive and rapid growing. They are refractory to chemotherapy, and have been posting the biggest challenge for the treatment of SS. The principal mechanism by which the Sézary cells develop resistance to chemotherapeutic agents is through the overexpression of ATP‐binding cassette (ABC) transporter proteins such as P‐glycoprotein (P‐gp), multidrug‐resistance associated protein 1 (MRP1), and breast cancer resistance protein (BCRP). The expressions of P‐gp, MRP1 and BCRP genes appear to be regulated, in part, by nuclear factor E2‐related factor 2 (Nrf2), a transcriptional regulator of cellular resistance to oxidants. α‐Mangostin (α‐MGT) is a xanthone derivative that possesses antioxidant and cytotoxic activities in various types of cancers. This study is undertaken to support the hypothesis that through its antioxidant activity, α‐MGT mediates downregulation of ABC transporters expression in HuT78, the cell line isolated from a Sézary patient. The results revealed that HuT78 cells expressed P‐gp, MRP1 and BCRP at various frequencies, ranging from 31% to 78% where the expression level of MRP1 was the highest followed by that of BCRP and P‐gp. Upon exposure of HuT78 cells to 12 μM α‐MGT for 24 hours, the expression of MRP1 was decreased by 50%, BCRP was slightly downregulated, and the P‐gp was undetectable. Our preliminary data suggested that α‐MGT may be beneficial in reversing the resistant phenotype of Sézary cells for chemotherapy.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.