Combination of an Oxindole Derivative with (−)-β-Elemene Alters Cell Death Pathways in FLT3/ITD+ Acute Myeloid Leukemia Cells

Abstract

Acute myeloid leukemia (AML) is one of the cancers that grow most aggressively. The challenges in AML management are huge, despite many treatment options. Mutations in FLT3 tyrosine kinase receptors make the currently available therapies less responsive. Therefore, there is a need to find new lead molecules that can specifically target mutated FLT3 to block growth factor signaling and inhibit AML cell proliferation. Our previous studies on FLT3-mutated AML cells demonstrated that β-elemene and compound 5a showed strong inhibition of proliferation by blocking the mutated FLT3 receptor and altering the key apoptotic genes responsible for apoptosis. Furthermore, we hypothesized that both β-elemene and compound 5a could be therapeutically effective. Therefore, combining these drugs against mutated FLT3 cells could be promising. In this context, dose–matrix combination-based cellular inhibition analyses, cell morphology studies and profiling of 43 different apoptotic protein targets via combinatorial treatment were performed. Our studies provide strong evidence for the hypothesis that β-elemene and compound 5a combination considerably increased the therapeutic potential of both compounds by enhancing the activation of several key targets implicated in AML cell death.

Discovery and Anticancer Screening of Novel Oxindole-Based Derivative Bearing Pyridyl Group as Potent and Selective Dual FLT3/CDK2 Kinase Inhibitor

“…Furthermore, it selectively targeted FLT3 ITD-mutated MV4-11 AML cells, with an IC 50 of 4.3 µM after 72 h [20,21]. In addition, we have documented a sequence of substances exhibiting encouraging anticancer properties specifically against the MCF-7 breast cancer cell line.…”

β-elemene alleviates esophageal fibrosis after endoscopic submucosal dissection via the FAP-mediated PTEN-PI3K/AKT signaling pathway

“…However, its specific mechanism in esophageal fibrosis remains unclear. Recent studies have shown that β-elemene effectively suppresses the aberrant activation of the PI3K-AKT pathway induced by FMS-like tyrosine kinase 3 (FLT3) mutations, leading to the inhibition of Acute myeloid leukemia (AML) cell proliferation [ [25] , [26] , [27] ]. It can be inferred that the PI3K/AKT signaling pathway may represent a downstream signaling cascade of for β-elemene.…”