sansalvamide-a and Pancreatic-Neoplasms

Heat shock protein 90 (Hsp90) plays a vital role in the progress of malignant disease and elevated Hsp90 expression has been reported in pancreatic cancer. In this study, we radiolabeled a dimeric Sansalvamide A derivative (Di-San A1) with

Topics: Animals; Cell Line, Tumor; Copper; Depsipeptides; Female; Gene Expression Regulation, Neoplastic; Heterografts; HSP90 Heat-Shock Proteins; Humans; Mice; Mice, Nude; Neoplasm Proteins; Neoplasm Transplantation; Pancreatic Neoplasms; Positron-Emission Tomography; Protein Multimerization

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.

Topics: Cell Cycle; Cell Growth Processes; Cell Line, Tumor; Cyclin A; Cyclin D1; Cyclin E; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Cyclin-Dependent Kinase Inhibitor p21; Depsipeptides; Down-Regulation; Humans; Pancreatic Neoplasms

We report an extensive structure-activity relationship (SAR) of 78 compounds active against two pancreatic cancer cell lines. Our comprehensive evaluation of these compounds utilizes SAR that allow us to evaluate which features of potent compounds play a key role in their cytotoxicity. This is the first report of 19 new second-generation structures, where these new compounds were designed from the first generation of 59 compounds. These 78 structures were tested for their cytotoxicity and this is the first report of their activity against two pancreatic cancer cell lines. Our results show that out of 78 compounds, three compounds are worth pursuing as leads, as they show potency of 55% in both cancer cell lines. These three compounds all have a common structural motif, two consecutive d-amino acids and an N-methyl moiety. Further, of these three compounds, two are second-generation structures, indicating that we can incorporate and utilize data from the first generation to design potency into the second generation. Finally, one analog is in the mid nanomolar range, and has the lowest IC(50) of any reported San A derivative. These analogs share no structural homology to current pancreatic cancer drugs, and are cytotoxic at levels on par with existing drugs treating other cancers. Thus, we have established Sansalvamide A as an excellent lead for killing multiple pancreatic cancer cell lines.

Topics: Antineoplastic Agents; Cell Line, Tumor; Depsipeptides; Drug Design; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Humans; Pancreatic Neoplasms; Structure-Activity Relationship

Thirty-one Sansalvamide A peptide derivatives were synthesized. (3)H thymidine inhibition assays were performed using two pancreatic cancer cell lines (PL45 and BxPC-3). Six compounds possess 140-fold increased differential selectivity for cancer cell lines over normal cell lines (WS1, skin fiberblasts) and are 140 times more active against pancreatic cancer cell lines than compounds used clinically to treat these cancers (e.g., 5-FU). Structure-activity relationship studies show the inclusion of a single N-methyl and/or d-amino acid appears to be critical for presenting the active conformation of the six San A peptide derivatives to their biological target(s).

Topics: Antineoplastic Agents; Cell Line, Tumor; Depsipeptides; Humans; Pancreatic Neoplasms; Structure-Activity Relationship

Patients with pancreatic cancer have little hope for cure because no effective therapies are available. Sansalvamide A is a cyclic depsipeptide produced by a marine fungus. We investigated the effect of a novel sansalvamide A analogue on growth, cell-cycle phases, and induction of apoptosis in human pancreatic cancer cells in vitro. The sansalvamide analogue caused marked time- and concentration-dependent inhibition of DNA synthesis and cell proliferation of two human pancreatic cancer cell lines (AsPC-1 and S2-013). The analogue induced G0/G1 phase cell-cycle arrest and morphological changes suggesting induction of apoptosis. Apoptosis was confirmed by annexin V binding. This novel sansalvamide analogue inhibits growth of pancreatic cancer cells through G0/G1 arrest and induces apoptosis. Sansalvamide analogues may be valuable for the treatment of pancreatic cancer.

Topics: Antineoplastic Agents; Cell Cycle; Cell Line; Cell Proliferation; Cell Survival; Depsipeptides; Dose-Response Relationship, Drug; Humans; Pancreatic Neoplasms