title: Disruption of actin filaments and suppression of pancreatic cancer cell viability and migration following treatment with polyisoprenylated cysteinyl amides.
abstract: Pancreatic cancer is characterized by K-Ras mutations in over 90% of the cases. The mutations make the tumors aggressive and resistant to current therapies resulting in very poor prognoses. Valiant efforts to drug mutant K-Ras and related proteins for the treatment of cancers with Ras mutations have been elusive. The need thus persists for therapies to target and suppress the hyperactive K-Ras mutant proteins to normal levels of activity. Polyisoprenylated cysteinyl amide inhibitors (PCAIs) of polyisoprenylated methylated protein methyl esterase (PMPMEase) were designed to disrupt polyisoprenylated protein metabolism and/or functions. The potential for PCAIs to serve as targeted anticancer agents for pancreatic cancer was evaluated in pancreatic ductal adenocarcinoma (PDAC) cell lines expressing mutant (MIAPaCa-2 and Panc-1) and wild type (BxPC-3) K-Ras proteins. The PCAIs inhibited MIAPaCa-2 and BxPC-3 cell viability and induced apoptosis with EC50values as low as 1.9 µM. The PCAIs, at 0.5 µM, inhibited MIAPaCa-2 cell migration by 50%, inhibited colony formation and disrupted F-actin filament organization. The PCAIs blocked MIAPaCa-2 cell progression at the G0/G1 phase. These results reveal that the PCAIs disrupt pertinent biological processes that lead to pancreatic cancer progression and thus have the potential to act as targeted effective treatments for pancreatic cancer.
authors.affiliation: College of Pharmacy and Pharmaceutical Sciences, Florida A&M University Tallahassee Florida 32307, USA.
authors.forename: Augustine T
authors.initials: AT
authors.lastname: Nkembo
authors.affiliation: College of Pharmacy and Pharmaceutical Sciences, Florida A&M University Tallahassee Florida 32307, USA.
authors.forename: Olufisayo
authors.initials: O
authors.lastname: Salako
authors.affiliation: College of Pharmacy and Pharmaceutical Sciences, Florida A&M University Tallahassee Florida 32307, USA.
authors.forename: Rosemary A
authors.initials: RA
authors.lastname: Poku
authors.affiliation: College of Pharmacy and Pharmaceutical Sciences, Florida A&M University Tallahassee Florida 32307, USA.
authors.forename: Felix
authors.initials: F
authors.lastname: Amissah
authors.affiliation: College of Pharmacy and Pharmaceutical Sciences, Florida A&M University Tallahassee Florida 32307, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Ntantie
authors.affiliation: College of Pharmacy and Pharmaceutical Sciences, Florida A&M University Tallahassee Florida 32307, USA.
authors.forename: Hernan
authors.initials: H
authors.lastname: Flores-Rozas
authors.affiliation: College of Pharmacy and Pharmaceutical Sciences, Florida A&M University Tallahassee Florida 32307, USA.
authors.forename: Nazarius S
authors.initials: NS
authors.lastname: Lamango
keywords: F-actin; PCAIs; PMPMEase; cell migration; cell proliferation; pancreatic cancer