Crocetinic acid inhibits hedgehog signaling to inhibit pancreatic cancer stem cells

Journal Reference

Oncotarget. 2015;6(29):27661-73.

Rangarajan P¹, Subramaniam D¹, Paul S², Kwatra D¹, Palaniyandi K², Islam S², Harihar S², Ramalingam S¹, Gutheil W³, Putty S³, Pradhan R⁴, Padhye S⁴,Welch DR^2,1, Anant S^2,1, Dhar A^2,1.

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1. Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS, USA.
2. Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS, USA.
3. Department of Pharmaceutical Sciences, University of Missouri at Kansas City, Kansas City, MO, USA.
4. Interdisciplinary Science and Technology Research Academy, Abeda Inamdar College, University of Pune, Pune, India.

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Abstract

Pancreatic cancer is the fourth leading cause of cancer deaths in the US and no significant treatment is currently available. Here, we describe the effect of crocetinic acid, which we purified from commercial saffron compound crocetin using high performance liquid chromatography. Crocetinic acid  inhibits proliferation of pancreatic cancer cell lines in a dose- and time-dependent manner. In addition, it induced apoptosis. Moreover, the compound significantly inhibited epidermal growth factor receptor and Akt phosphorylation. Furthermore, crocetinic acid decreased the number and   size of the pancospheres in a dose-dependent manner, and suppressed the expression of the marker protein DCLK-1 (Doublecortin Calcium/Calmodulin-Dependent Kinase-1) suggesting that crocetinic acid  targets cancer stem cells (CSC). To understand the mechanism of CSC inhibition, the signaling pathways affected by purified crocetinic acid were dissected. Sonic hedgehog (Shh) upon binding to its cognate receptor patched, allows smoothened to accumulate and activate Gli transcription factor. Crocetinic acid inhibited the expression of both Shh and smoothened. Finally, these data were confirmed in vivo where the compound at a dose of 0.5 mg/Kg bw suppressed growth of tumor xenografts. Collectively, these data suggest that purified crocetinic acid inhibits pancreatic CSC, thereby inhibiting pancreatic tumorigenesis.

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