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Am J Cancer Res. 2018 Nov 1;8(11):2267-2283. eCollection 2018.

Multiple mechanisms involved in a low concentration of FL118 enhancement of AMR-MeOAc to induce pancreatic cancer cell apoptosis and growth inhibition.

Author information

1
Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center Buffalo, NY 14263, USA.

Abstract

Activating mutations in GTPase protein KRAS occurs in approximately 90% of pancreatic cancers. Mutated KRAS lead to constitutive activation of RAF/MEK/ERK and PI3K/Akt pathways in pancreatic cancer. There is currently no effective KRAS-targeted therapeutics available in the clinic for treating this subset of cancer. In this study we demonstrate that combination of a plant-isolated triterpenoid compound AMR-MeOAc with a low concentration of an antiapoptotic protein inhibitor, FL118 exhibited synergistic cytotoxic activity against pancreatic cancer cells with either mutant KRAS (HPAF-II, KRASG12D) or wild type KRAS (BxPC-3, KRASWT). In pancreatic cancer cells with mutant KRASG12D, AMR-MeOAc and FL118 acting together to inhibit the constitutive KRASG12D mutant activity, increase the reactive oxygen species (ROS) formation, apoptosis induction, and decrease of the expression of survivin and XIAP, while strongly inducing Bax. These effects were also associated with the decrease of B-RAF, ERK and p-ERK. Additionally, AMR-MeOAc and FL118 alone or in combination inhibited the constitutive activation of NF-κB in BxPC-3 cells, which suggests that inhibition of NF-κB in BxPC-3 cells by AMR-MeOAc and FL118 may also be a part of the mechanism of action, when pancreatic cancer cells possess wild type KRAS. Together, the novel combination treatment might provide an effective strategy to overcome the KRASG12D mutant-mediated and NF-κB activation-mediated resistance in pancreatic cancer with either KRASG12D mutation or NF-κB activation/wild type KRAS.

KEYWORDS:

AMR-MeOAc; ERK; FL118; KRASG12D; NF-κB; XIAP; pancreatic cancer; reactive oxygen species (ROS); survivin

PMID:
30555743
PMCID:
PMC6291652

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