Cytotoxic Mechanism of Momilactones A and B against Acute Promyelocytic Leukemia and Multiple Myeloma Cell Lines

SIMPLE SUMMARY: Though the anticancer potentiality of momilactones has been reported in several studies, their cytotoxic mechanism has not been comprehensively scrutinized. In this study, we investigated the cytotoxicity of momilactones A (MA) and B (MB) against acute promyelocytic leukemia (APL) HL-60 and multiple myeloma (MM) U266 cell lines. According to MTT results, MB and the mixture MAB (1:1, w/w) show a substantial inhibition on the cell viability of HL-60 and U266, with IC(50) ranging from 4.49 to 5.59 µM. Besides, MB and MAB at 5 µM inhibit HL-60 cells through the regulations of relevant proteins to apoptosis-inducing factors (p-38, BCL-2, and caspase-3) and cell cycle arrest at G2 phase (p-38, CDK1, and cyclin B1). Meanwhile, these compounds enhance U266 apoptosis by altering p-38, BCL-2, and caspase-3 signaling pathways. Significantly, momilactones exhibit a minor effect on a non-cancerous cell line (MeT-5A), implying that they are promising candidates for developing novel anti-APL and anti-MM medicines. ABSTRACT: This is the first study clarifying the cytotoxic mechanism of momilactones A (MA) and B (MB) on acute promyelocytic leukemia (APL) HL-60 and multiple myeloma (MM) U266 cell lines. Via the MTT test, MB and the mixture MAB (1:1, w/w) exhibit a potent cytotoxicity on HL-60 (IC(50) = 4.49 and 4.61 µM, respectively), which are close to the well-known drugs doxorubicin, all-trans retinoic acid (ATRA), and the mixture of ATRA and arsenic trioxide (ATRA/ATO) (1:1, w/w) (IC(50) = 5.22, 3.99, and 3.67 µM, respectively). Meanwhile MB, MAB, and the standard suppressor doxorubicin substantially inhibit U266 (IC(50) = 5.09, 5.59, and 0.24 µM, respectively). Notably, MB and MAB at 5 µM may promote HL-60 and U266 cell apoptosis by activating the phosphorylation of p-38 in the mitogen-activated protein kinase (MAPK) pathway and regulating the relevant proteins (BCL-2 and caspase-3) in the mitochondrial pathway. Besides, these compounds may induce G2 phase arrest in the HL-60 cell cycle through the activation of p-38 and disruption of CDK1 and cyclin B1 complex. Exceptionally, momilactones negligibly affect the non-cancerous cell line MeT-5A. This finding provides novel insights into the anticancer property of momilactones, which can be a premise for future studies and developments of momilactone-based anticancer medicines.