Rangarajan Parthasarathy, Subramaniam Dharmalingam, Paul Santanu, Kwatra Deep, Palaniyandi Kanagaraj, Islam Shamima, Harihar Sitaram, Ramalingam Satish, Gutheil William, Putty Sandeep, Pradhan Rohan, Padhye Subhash, Welch Danny R, Anant Shrikant, Dhar Animesh
Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS, USA.
Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS, USA.
Oncotarget. 2015 Sep 29;6(29):27661-73. doi: 10.18632/oncotarget.4871.
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.
胰腺癌是美国癌症死亡的第四大主要原因，目前尚无有效的治疗方法。在此，我们描述了西红花酸的作用，我们使用高效液相色谱法从商业藏红花化合物藏红素中纯化得到了该物质。西红花酸以剂量和时间依赖性方式抑制胰腺癌细胞系的增殖。此外，它还诱导细胞凋亡。而且，该化合物显著抑制表皮生长因子受体和Akt磷酸化。此外，西红花酸以剂量依赖性方式减少胰腺球的数量和大小，并抑制标记蛋白DCLK-1（双皮质素钙/钙调蛋白依赖性激酶-1）的表达，这表明西红花酸靶向癌症干细胞（CSC）。为了了解CSC抑制的机制，我们剖析了纯化的西红花酸影响的信号通路。音猬因子（Shh）与其同源受体patched结合后，使smoothened积累并激活Gli转录因子。西红花酸抑制Shh和smoothened的表达。最后，这些数据在体内得到证实，该化合物以0.5mg/Kg体重的剂量抑制肿瘤异种移植的生长。总体而言，这些数据表明纯化的西红花酸抑制胰腺CSC，从而抑制胰腺肿瘤发生。
