Curcumin induces apoptosis by inhibiting BCAT1 expression and mTOR signaling in cytarabine‑resistant myeloid leukemia cells

Abstract

Cytarabine is a key chemotherapy drug for treating leukemia; however, chemotherapy-induced multidrug resistance is a major cause of therapy failure or tumor recurrence. Current medical treatment strategies still cannot address the issue of multidrug resistance phenotypes in the treatment of leukemia. Curcumin counteracts tumor development by inducing apoptosis in cytarabine-resistant acute myeloid leukemia cells. Branched-chain amino acid transaminase 1 (BCAT1), an aminotransferase enzyme, acts on branched-chain amino acids. Moreover, the aberrant expression of BCAT1 has been observed in numerous cancer cells, and BCAT1 serves a critical role in the progression of myeloid leukemia. BCAT1 can interfere with cancer cell proliferation by regulating mTOR-mediated mitochondrial biogenesis and function. The present study aimed to investigate whether curcumin induces apoptosis by regulating BCAT1 expression and mTOR signaling in cytarabine-resistant myeloid leukemia cells. Four leukemia cell lines and three primary myeloid leukemia cells were treated with curcumin, and the expression and activity of BCAT1 and mTOR were investigated by reverse transcription-quantitative PCR, western blotting and α-KG quantification assay. The results demonstrated that curcumin inhibited BCAT1 expression in Kasumi-1, KG-1, HL60, cytarabine-resistant HL60, and cytarabine-resistant primary myeloid leukemia cells. Notably, tetrahydrocurcumin, a major metabolite of curcumin, and cytarabine had no inhibitory effect on BCAT1 expression. Furthermore, BCAT1 and mTOR signaling may modulate each other in cytarabine-resistant HL60 cells. The present results indicated that curcumin may induce apoptosis by inhibiting the BCAT1 and mTOR pathways. Thus, understanding the mechanism underlying curcumin-induced apoptosis in cytarabine-resistant cells can support the development of novel drugs for leukemia.

Curcumin in treatment of hematological cancers: Promises and challenges

“…Curcumin-mediated inhibition of BCAT1 and mTOR triggers apoptosis in leukemia cells. 44 Although most of the studies have focused on apoptosis as a kind of cell death regulated by curcumin in affecting leukemia progression, autophagy is also associated with cell death. It has been shown that curcumin and tetrahydrocurcumin have capacity of inducing both autophagy and apoptosis in reducing progression of leukemia cells and decreasing their survival rate.…”

The mechanism of branched-chain amino acid transferases in different diseases: Research progress and future prospects

“…The activated BCAT1 cooperated with increased Glu to promote the transamination of BCKA, maintaining the cellular BCAA pool (44). In addition, one study reported that curcumin reduced a-KG levels by inhibiting BCAT1 expression and the mTOR pathway, and finally induced apoptosis in cytarabine-resistant ML cancer cells (45).…”

Prediction of miRNA‑mRNA network regulating the migration ability of cytarabine‑resistant HL60 cells

“…The standard therapeutic approach for AML is cytarabine-based therapy that starts with induction chemotherapy [continuous infusion of cytarabine for 7 days concurrent with short infusions of anthracycline on each of the first 3 days (7+3 regimen)], followed by several cycles of consolidation chemotherapy or allogeneic HSC transplantation ( 3 , 4 ). However, only ~70% of patients receiving standard induction therapy achieve complete remission, and only 40% become long-term survivors ( 3 , 5 ). Older patients with AML exhibit stronger intrinsic resistance and less tolerance to chemotherapy than younger patients, resulting in a poor response to standard induction therapy ( 6 ).…”