A novel sansalvamide analogue inhibits pancreatic cancer cell proliferation via induction of macrophage inhibitory cytokine (MIC-1)

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Introduction: Pancreatic cancer continues to be a devastating disease with a poor prognosis and survival. Novel therapeutics are currently under investigation. Sansalvamide A is a cyclic peptide from a marine fungus and has potent anti-proliferative activity in cancer cells. Macrophage inhibitory cytokine (MIC-1) is a member of the transforming growth factor beta superfamily and is associated with pro-apoptotic and anti-tumorigenic activities. In the present study, we investigated the growth-inhibitory effects of a novel brominated and methylated sansalvamide depsipeptide analogue on human pancreatic cancer cells and the role of MIC-1 in this growth inhibition. Methods: Human pancreatic cancer (ASPC-1) cells were treated with 10 μM sansalvamide analogue and cell counting was conducted at 24, 48 and 72 hours. Olignonucleotide microarray analysis was conducted to identify genes whose expression is markedly changed by the sansalvamide depsipeptide. Real-time RT-PCR was performed after 24 hours to confirm the time and concentration-dependent up-regulation of one particular gene, MIC-1. ASPC-1 cells were also pre-treated with actinomycin D (an inhibitor of transcription) to determine the role of transcription and message stability in sansalvamide analogue-induced MIC-1 expression. Results: The sansalvamide depsipeptide analogue significantly inhibited cell proliferation (93% decrease in cell number at 72 hours with 10μM, P<0.01). The sansalvamide depsipeptide analogue caused concentration and time-dependent induction of MIC-1 expression (5.1 fold increase at 3 hours, 14.0 fold increase at 6 hours, 10.3 fold increase at 12 hours and 6.3 fold increase at 24 hours with 10 μM, P <0.01 ). In cells pre-treated with actinomycin D, the sansalvamide depsipeptide analogue inhibits the induction of MIC-1, suggesting that a change in transcription is involved. Conclusions: The sansalvamide analogue induced growth inhibition and up-regulated MIC-1 gene expression at the transcriptional level in human pancreatic cancer cells. Furthermore, the growth inhibition is associated with increased expression of MIC-1.