Novel synthetic oleanane triterpenoid AMR-MeOAc inhibits K-Ras through ERK, Akt and survivin in pancreatic cancer cells.
K-Ras activating mutations are a major problem that drives aggressive tumor growth and metastasis in pancreatic cancer. Currently, there are no effective targeted therapies for this genetically defined subset of cancers harboring oncogenic K-Ras mutations that confer drug resistance, aggressive tumor growth, metastasis and poor clinical outcome. We identified a novel synthetic oleanane triterpenoid compound designated AMR-MeOAc that effectively kills K-Ras mutant pancreatic cancer HPAF-II cells. The cytotoxic effects correlated with apoptosis induction, as was evidenced by increase of apoptosis cells upon the treatment of AMR-MeOAc in HPAF-II cells. Our studies revealed that AMR-MeOAc treatment inhibits cancer associated survival gene survivin. Moreover, AMR-MeOAc also led to down regulation of Akt, ERK1/2 and survivin protein levels. Our results indicate that AMR-MeOAc or its active analogs could be a novel class of anticancer agents against K-Ras driven human pancreatic cancer.
Siddha Clinic and Research Center SVA, Kanyakumari, India. Electronic address: thangaiyanrabi@hotmail.com.
Thangaiyan
T
Rabi
Captain Srinivasamurthy Drug Research Institute for Ayurveda, Chennai, India.
Mathuram
M
Venkatanarashiman
D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002277:Carcinoma / Q000378:metabolism; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D064368:Healthy Volunteers; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D029582:Meliaceae / Q000737:chemistry*; D010190:Pancreatic Neoplasms / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D000077022:Survivin; D014315:Triterpenes / Q000138:chemical synthesis* / Q000737:chemistry; D018631:ras Proteins / Q000037:antagonists & inhibitors*
D000972:Antineoplastic Agents, Phytogenic; C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D000077022:Survivin; D014315:Triterpenes; C453733:amooranin; D051057:Proto-Oncogene Proteins c-akt; D018631:ras Proteins
AMR-MeOAc; Apoptosis; ERK1/2 and Akt1; K-Ras activating mutations; Pancreatic cancer; Survivin