Quassinoid analogs with enhanced efficacy for treatment of hematologic malignancies target the PI3Kγ isoform

Abstract

Development of novel PI3K inhibitors is an important strategy to overcome their resistance and poor tolerability in clinical trials. The quassinoid family member Brusatol shows specific inhibitory activity against hematologic malignancies. However, the mechanism of its anti-cancer activity is unknown. We investigated the anti-cancer activity of Brusatol on multiple hematologic malignancies derived cell lines. The results demonstrated that the PI3Kγ isoform was identified as a direct target of Brusatol, and inhibition was dramatically reduced on cells with lower PI3Kγ levels. Novel synthetic analogs were also developed and tested in vitro and in vivo. They shared comparable or superior potency in their ability to inhibit malignant hematologic cell lines, and in a xenograft transplant mouse model. One unique analog had minimal toxicity to normal human cells and in a mouse model. These new analogs have enhanced potential for development as a new class of PI3K inhibitors for treatment of hematologic malignancies.

Brusatol modulates diverse cancer hallmarks and signaling pathways as a potential cancer therapeutic

“…Similar results have also been found in NPC (CNE-1), with a decrease in cyclin B1, cyclin D1, Cdc2, and Cdc25c, and an increase in p-Cdc2; the cells also are arrested in only one phase [60]. In other cancer types, brusatol exerts an anti-proliferative effect by interfering with the cell cycle, including G0/G1 phase in the PC9 and HCC827GRKU lung cancer cell lines [21,54], and the Raji and SU-DHL-4 lymphoma cell lines [45], and G2/M phase in the pancreatic cancer lines Capan-2 and PANC-1 [63]. In A375 melanoma cells, Wang et al have found that cyclin D1, cyclin E2, CDK4 and CDK6 decrease after brusatol treatment, thus causing G0/G1 cell-cycle arrest [67].…”

“…Pei et al have reported that brusatol arrests cells at G0/ G1 phase in vitro and suppresses cancer growth in vivo [45]. Mata-Greenwood et al have shown that brusatol induces leukemic cell differentiation and G1 cell-cycle arrest, which are associated with the downregulation of c-myc [48].…”

“…Brusatol arrests lymphoma cells at G0/G1 by specifically targeting the PI3K/AKT pathway [45]. In addition, brusatol suppresses cell viability and growth by increasing oxidative stress in multiple myeloma cells [59].…”

Potential entry receptors for human γ-herpesvirus into epithelial cells: A plausible therapeutic target for viral infections

“…Since Eph and ephrins have a remarkable role in infectious diseases it has been increasingly recognized as an attractive therapeutic target for many diseases which includes anticancer therapeutics, synaptic plasticity modulators, homeostasis of bone, and the stem cell biology [ 21 , 116 , 155 ]. Most of the kinase inhibitors possess poor selectivity and target multiple kinases.…”

Targeted Therapies for Epstein-Barr Virus-Associated Lymphomas

“…This may further inhibit TGF-β1 (transforming growth factor beta 1) mediated apoptosis and promote cell survival for lymphomagenesis [ 12 ]. Our recent study demonstrated that PI3Kγ is a potential target of Brusatol and its derived analogs in EBV-positive lymphomas [ 13 ]. Additionally, other important WNT and MAPK (mitogen-activated protein kinase) signaling pathways are also hijacked by EBV latent proteins to exhibit hallmarks of cancer during lymphomagenesis [ 14 , 15 ].…”