Abstract 3734: Cancer stem cells: novel chemopreventive targets for pancreatic cancer.
Authors: Rangarajan Parthasarathy , Subramaniam Dharmalingam , Kwatra Deep , Islam Shamima , Palaniyandi Kanagaraj , Anant Shrikant , Dhar Animesh 
Published: August 2014

Pancreatic cancer is the fourth leading cause of mortality in the United States and no significant treatment is currently available. Although an increasing number of therapeutic options exist for patients with advanced disease, their efficacy is time limited and non-curative. Presently approximately close to 60% of cancer patients in the United States are believed to utilize therapies derived from plants, herbs, flowers, or nutrients either exclusively or concurrently with traditional chemotherapy or radiation therapy.

Recent evidence suggests the existence of a small population of tumorigenic stem cells responsible for tumor initiation, metastasis and resistance to chemotherapy and radiation. Identification of the regulatory mechanisms and signaling pathways involved in cancer stem cells (CSCs) will help in designing novel agents to target this refractory cell population in pancreatic cancers.

We are currently investigating the mechanisms by which purified crocetinic acid, a carotenoid molecule isolated from saffron, inhibits growth of pancreatic cancer in vitro and in vivo models. Our studies demonstrate that the compound had significant cytotoxicity against pancreatic cancer cells in both a dose- and time-dependent manner. Pancreatic CSCs can be allowed to divide and grow in ultra-low binding tissue culture dishes to form multicellular spheroids called pancospheres. Treatment with purified crocetinic acid decreased the number and size of the primary and secondary pancospheres in a dose dependent manner, suggesting that crocetinic acid targets CSCs. To understand the mechanism of inhibition of pancospheres, the signaling pathways affected by crocetinic acid were dissected. Aberrant activation of Sonic Hedgehog signaling pathway has been associated with renewal of cancer stem cells, and in the development of several solid cancers. Sonic hedgehog (Shh) upon binding to its cognate receptor patched, allows smoothened to accumulate and activate Gli transcription factor. Treatment with crocetinic acid inhibited the expression of both Shh and smoothened in the pancreatic CSCs with concomitant reduction of the expression of a novel pancreatic CSC marker, DCLK-1 (Doublecortin Calcium/Calmodulin-Dependent Kinase-1). Furthermore, it inhibited the expression of patched-1 and Gli-1, downstream targets of the hedgehog signaling pathway. Crocetinic acid also inhibited tumor formation in pancreatic cancer in vivo xenograft models.

Taken together, these data suggest that crocetinic acid effectively inhibits pancreatic CSCs by down regulating the sonic hedgehog pathway, thereby inhibiting tumorigenesis.

Citation Format: Parthasarathy Rangarajan, Dharmalingam Subramaniam, Deep Kwatra, Shamima Islam, Kanagaraj Palaniyandi, Shrikant Anant, Animesh Dhar. Cancer stem cells: novel chemopreventive targets for pancreatic cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3734. doi:10.1158/1538-7445.AM2013-3734