Glaucarubinone and gemcitabine synergistically reduce pancreatic cancer growth via down-regulation of P21-activated kinases.
Pancreatic cancer is one of the most lethal of human malignancies. Nearly 100% cases of pancreatic cancer carry mutations in KRas. P-21-activated kinases (PAKs) are activated by and act downstream of KRas. Glaucarubinone, a natural product first isolated from the seeds of the tree Simarouba glauca, was originally developed as an antimalarial drug, and has more recently been recognised as an anticancer agent. The aims of this study were to determine whether glaucarubinone, alone or in combination with the front-line chemotherapeutic agent gemcitabine, would inhibit the growth of pancreatic cancer cells in vitro or in vivo and the mechanism involved. Growth of the human pancreatic cancer cell lines PANC-1 and MiaPaCa-2 was measured by (3)H-thymidine incorporation in vitro, and by volume as xenografts in SCID mice. The expression and activities of the two serine/threonine kinases PAK1 and PAK4, which are key regulators of cancer progression, were measured by Western blotting. Here we report that glaucarubinone decreased proliferation and migration of pancreatic cancer cells in vitro, and reduced their growth as xenografts in vivo. Treatment with glaucarubinone and gemcitabine reduced proliferation in vitro and tumor growth in vivo more than treatment with either glaucarubinone or gemcitabine alone. Treatment with glaucarubinone reduced PAK1 and PAK4 activities, which were further decreased by the combination of glaucarubinone and gemcitabine. These results indicate that glaucarubinone reduced pancreatic cancer cell growth at least in part via inhibition of pathways involving PAK1 and PAK4. The synergistic inhibition by glaucarubinone and gemcitabine observed both in vitro and in vivo suggests that glaucarubinone may be a useful adjunct to current regimes of chemotherapy.
Department of Surgery, University of Melbourne, Austin Health, Melbourne, Victoria 3084, Australia.
Dannel
D
Yeo
Department of Surgery, University of Melbourne, Austin Health, Melbourne, Victoria 3084, Australia.
Nhi
N
Huynh
Molecular Targets Laboratory, National Cancer Institute, Frederick, MD 21702, United States.
John A
JA
Beutler
Department of Surgery, University of Melbourne, Austin Health, Melbourne, Victoria 3084, Australia.
Christopher
C
Christophi
Department of Surgery, University of Melbourne, Austin Health, Melbourne, Victoria 3084, Australia.
Arthur
A
Shulkes
Department of Surgery, University of Melbourne, Austin Health, Melbourne, Victoria 3084, Australia.
Graham S
GS
Baldwin
Department of Surgery, University of Melbourne, Austin Health, Melbourne, Victoria 3084, Australia.
Mehrdad
M
Nikfarjam
Department of Surgery, University of Melbourne, Austin Health, Melbourne, Victoria 3084, Australia. Electronic address: hong.he@unimelb.edu.au.
Hong
H
He
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D004357:Drug Synergism; D004789:Enzyme Activation; D005900:Glaucarubin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D023041:Xenograft Model Antitumor Assays; D054462:p21-Activated Kinases / Q000378:metabolism*; D000093542:Gemcitabine
D050759:Cyclin-Dependent Kinase Inhibitor p21; D003841:Deoxycytidine; C015235:glaucarubinone; D054462:p21-Activated Kinases; D005900:Glaucarubin; D000093542:Gemcitabine
Gemcitabine; Glaucarubinone; P21-activated kinases; Pancreatic cancer