A Tumor Homing Peptide-Linked Arsenic Compound Inhibits Pancreatic Cancer Growth and Enhances the Inhibitory Effect of Gemcitabine

Arsenic trioxide (ATO) has been shown to inhibit pancreatic cancer (PC) cell growth <i>in vitro</i> and to promote the inhibitory effects of gemcitabine (Gem) on PC <i>in vivo</i>. However, the high toxicity of ATO associated with the required high doses and indiscriminate targeting has limited its clinical application. This study aimed to determine whether coupling arsenic to a tumor homing peptide would increase the inhibitory potency against PC cells. The effects of this peptide-linked arsenic compound (PhAs-LHP), the analogous non-targeting arsenic compound (phenylarsine oxide, PAO), and marketed ATO on PC growth were tested <i>in vitro</i> and in a mouse model. The data demonstrated that PhAs-LHP inhibited PC cell growth <i>in vitro</i> more potently, with IC₅₀ values 10 times lower than ATO. Like ATO, PhAs-LHP induced cell death and cell cycle arrest. This cytotoxic effect of PhAs-LHP was mediated via a macropinocytosis-linked uptake pathway as amiloride (a macropinocytosis inhibitor) reduced the inhibitory effect of PhAs-LHP. More importantly, PhAs-LHP inhibited PC growth in mice and enhanced the inhibitory effect of Gem on PC growth at 2 times lower molar concentration than PAO. These results indicate that PhAs-LHP inhibited PC more potently than ATO/PAO and suggest a potential clinical use for the combination of Gem with the peptide-linked arsenic compound for the treatment of pancreatic cancer.