A translational investigation of natural products in treatment cancer cells: Hepatoma and Glioma

Abstract

Hepatocellular carcinoma (HCC) and Glioblastoma multiforme (GBM) and are common and aggressive primary malignant tumors in adults. Despite standard treatment including surgery, radiotherapy and targeted treatment, the prognosis for HCC and GBM patients are dismal, and there is a need for novel treatments. Natural compounds have been shown to be useful either alone or in combination with conventional therapies for the prevention of tumor progression and/or treatment of human malignancies. Therefore, the objective of this study was to translational investigation of natural products in treatment cancer cells: Hepatoma and Glioma. There are three topics included in this study: (1) The use of Destruxin (DB) in HCC treatment. (2) The use of Pterostilbene (PT) in HCC treatment. (3) The use of Pterostilbene (PT) in GBM treatment. Our studies revealed that (1) destruxin B (DB) inhibits the proliferation and induces the apoptosis of HCC cells by decreasing anti-apoptotic Bcl-2 and Bcl-xL and increasing proapoptotic Bax. DB also attenuates Wnt-signaling in HCC cells by downregulating β- catenin, Tcf4, and β-catenin/Tcf4 transcriptional activity, which results in the decreased expression of β-catenin target genes, such as cyclin D1, c-myc, and survivin. Furthermore, DB affects the migratory and invasive abilities of Sk-Hep1 cells through the suppression of markers of the epithelial-mesenchymal transition (EMT). A synergistic anti-proliferative and migratory effect was achieved by using the combination of DB and sorafenib. (2). To improve the outcome of treatment HCC, the effects of PT was investigated in combination with irradiation. For many malignancies, radiation therapy remains the second option only to surgery. However, radiation-induced tumor cell death is limited by a number of factors including intrinsic or acquired mechanisms of evasive resistance and the existence of cancer stem cells (CSCs). In this study, the different dosages of irradiation led to the enrichment of CD133+ Mahlavu and SK-Hep1 cells by flow cytometric analysis. CD133+ cells with CSC properties exhibited the high expression of stemness genes, selfrenewal, migration/invasion abilities and radiation resistance. Pterostilbene (PT) dose dependently reduced the enrichment of CD133+ in Mahlavu and SK-Hep1 cells upon irradiation; PT treatment also inhibited sphere formation, reduced stemness gene expression, and suppressed invasion and migration abilities as well as increasing apoptosis of HCC- CSCs. Based on our previous data, we used this model to apply on Glioblastoma multiforme (GBM) in which radiation was an indispensable tool of therapeutic regimens. Glioma stem cells (GSCs) with CD133+ have been shown to contribute to tumorigenesis, recurrence and treatment resistance. (3). Thus, a better understanding and the development of agents which target GSCs could potentially improve on treating GBM patients. Here, we demonstrated that GRP78 (an anti-stress protein) was highly expressed in GBM cells along with β- catenin and Notch and correlated to the development of GSCs. CD133+ GSCs exhibited enhanced migration/invasion and self-renewal abilities. When GRP78 was silenced, GSC properties were suppressed and the sensitivity to irradiation increased. In addition, the level of microRNA 205 appeared to be negatively associated with GRP78 expression. Interestingly, PT-treated GSCs exhibited suppressed self-renewal and irradiation-resistant abilities. PT-mediated effects were associated with induction miR-205. Finally, we showed that PT treatment suppressed tumorigenesis in GSC xenograft mice. Taken together, natural compound DB or PT may be considered for combination therapy to enhance the effect of sorafenib in HCC that of irradiation in GBM patients.