Sansalvamide induces pancreatic cancer growth arrest through changes in the cell cycle.
Survival of patients with pancreatic cancer remains poor due to inadequate chemotherapeutic options. Sansalvamide A, a cyclic depsipeptide produced by a marine fungus, has demonstrated significant anticancer activity. We previously observed antiproliferative effects in a series of sansalvamide A analogs in pancreatic cancer cells, one of which was further evaluated in this study. Two human pancreatic cancer cell lines (AsPC-1 and CD18) were incubated with increasing concentrations (10-50 muM) of the sansalvamide analog. Cell proliferation was then measured by thymidine incorporation and cell counting, and cell cycle analysis was determined by flow cytometry. Western blot analysis was used to evaluate expression of cyclin D1, cdk4, cdk6, cyclin E, cyclin A, cdk2, and p21. Sansalvamide caused G(1) phase cell cycle arrest in both cell lines, and Western blot analyses demonstrated up-regulation of p21, down-regulation of cyclins D1, E, and A, and cdk4, consistent with G(0)/G(1) cell cycle arrest. Cumulatively the results show that Sansalvamide A attenuates pancreatic cancer cell growth and represents a potential anticancer therapy.
Department of Surgery, Feinberg School of Medicine, Northwestern University, Suite 650, 676 N Saint Clair, Chicago, IL 60611, USA.
Michael J
MJ
Heiferman
Mohammad R
MR
Salabat
Michael B
MB
Ujiki
Matthew J
MJ
Strouch
Eric C
EC
Cheon
Richard B
RB
Silverman
David J
DJ
Bentrem
D002453:Cell Cycle / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D019925:Cyclin A / Q000096:biosynthesis; D019938:Cyclin D1 / Q000096:biosynthesis; D019927:Cyclin E / Q000096:biosynthesis; D051358:Cyclin-Dependent Kinase 4 / Q000096:biosynthesis; D051361:Cyclin-Dependent Kinase 6 / Q000096:biosynthesis; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis; D047630:Depsipeptides / Q000737:chemistry / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects; D006801:Humans; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
C493956:CDKN1A protein, human; D019925:Cyclin A; D019927:Cyclin E; D050759:Cyclin-Dependent Kinase Inhibitor p21; D047630:Depsipeptides; C119376:sansalvamide A; D019938:Cyclin D1; C495900:CDK4 protein, human; C495911:CDK6 protein, human; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6