The antitumor effect of the novel agent MCL/ACT001 in pancreatic ductal adenocarcinoma

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a major challenge in cancer therapy, there are more than four hundred thousand deaths a year and the 5-year survival rate less than 10%. The incidence continues to rise. Treatment with classic drugs offers limited therapeutic bene ts. The aim of this study was to investigate a new agent ACT001, the active metabolite is Micheliolide (MCL), study the mechanism and effect in vitro and in vivo against PDAC. MethodsMTT assay, wound healing assay and ow cytometry were used to assess the effects of MCL/ACT001 in vitro. DCFH-DA assay was to assess ROS accumulation. Western blotting, Immunohistochemical staining and TUNEL assay were also conducted to determine the mechanisms. PANC-1-Luc cells and bioluminescent reporter imaging were used to assess anti-tumor effect of ACT001 using a GSC orthotopic xenograft model in vivo. ResultsMCL/ACT001 inhibited cell growth in PDAC in a dose-dependent manner signi cantly, induced cell apoptosis, cell migration and reactive oxygen species (ROS) accumulation in vitro. In vivo, ACT001 (400 mg/kg/day) inhibited PDAC tumor growth in orthotopic xenograft mice. We veri ed that EGFR, Akt were overexpressed in PDAC cells and patient tumors markedly. Mechanism investigations revealed that MCL exerted its anti-tumor activity via regulation of EGFR-Akt-Bim signaling pathway thus inducing Bim expression both in vitro and in vivo. ConclusionMCL/ACT001 is a highly promising agent in the treatment of PDAC patients.

MCL attenuates atherosclerosis by suppressing macrophage ferroptosis via targeting KEAP1/NRF2 interaction

“…Micheliolide (MCL), which is derived from parthenolide, is a compound with antioxidant and anti-inflammatory effects and has multiple roles in tumors and inflammatory diseases [ 19 ]. ACT001 is a derivate of MCL, MCL/ACT001 is currently in phase II clinical trials for the treatment of glioblastoma (GBM) and has demonstrated anti -GBM activity [ 20 , 21 ]. Moreover, previous literature also suggested that MCL could be used as a specific inhibitor of NF-κB to inhibit the expression of inflammatory factors [ [22] , [23] , [24] ].…”

Pharmacological potential of micheliolide: A focus on anti-inflammatory and anticancer activities

“…Juan Yang et al, investigated the antitumor effect of the novel agent MCL/ACT001 in pancreatic ductal adenocarcinoma (PDAC), inducing cell apoptosis, cell migration, and ROS accumulation in vitro. Overall, their mechanistic investigations revealed that MCL exerted its antitumor activity via regulation of the EGFR-Akt-Bim signaling pathway, thus inducing Bim expression both in vitro and in vivo [ 93 ].…”

Exosomal miR-125b-5p derived from cancer-associated fibroblasts promotes the growth, migration, and invasion of pancreatic cancer cells by decreasing adenomatous polyposis coli (APC) expression

“…T h e 5 -y e a r s u r v i v a l r a t e o f p a n c r e a t i c d u c t a l adenocarcinoma (PDAC) is about 10%, highlighting its lethality (1). Micrometastasis is the most common type of metastasis and the primary cause of mortality in pancreatic ductal adenocarcinoma (PDAC) (2).…”