Anti-Cancer Activity of Cucurbitacin IIa

Abstract

Cancer is a debilitating disease resulting from uncontrolled proliferation. One major treatment strategy for cancer is the application of chemotherapeutic drugs which kill cancer cells. Cucurbitacins are a new family of plant-derived drugs that are being researched for their potential cytotoxic effects against cancer cells. All cucurbitacins have shared an anti-cancer activity stemming from their inhibitory effects on Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling. Cucurbitacin IIa (Cuc IIa) is the newest compound to be characterized in this family. The purpose of this thesis is to investigate the anti-cancer properties of Cuc IIa. Cuc IIa was used to treat mice that had been injected with Lewis Lung cancer cells. These animal studies show that Cuc IIa had reduced the tumor size without any weight change within the mouse. Furthermore, Cuc IIa displays anti-cancer activity against prostate cancer cell lines, PC3 and Rv1, and lung cancer cell line NCI-H1299. Cuc IIa is shown to induce apoptosis through actin clustering. In addition, Cuc IIa induces apoptosis through the increase in cleaved PARP expression and a reduction in phospho-Histone H3 expression. Cuc IIa induces cell cycle arrest at the G2/M phase of the cell cycle. While other members of the Cucurbitacin family express anti-cancer activity through effects on the JAK2/STAT3 pathway, Cuc IIa does not share this feature. Western blot staining for JAK2 and STAT3 proteins reveal that Cuc IIa exterts no direct effect JAK2/STAT3 phosphorylation. Instead, Cuc IIa inhibits survivin downstream of JAK2/STAT3 phosphorylation. Therefore, this thesis highlights a unique Cuc compound with the potential to become a powerful anti-cancer agent not working at the level of JAK2/STAT3 activation which is commonly found in other Cucurbitacins. This feature may provide a new mechanistic point of anti-cancer drug action to combat drug resistance.