Development of anti-angiogenic and pro-apoptotic agents from natual products for the treatment of cancer

Abstract

Cytotoxic drugs have contributed greatly to cancer treatment. However, their significant side effects always hamper their use in the clinical practice. In the recent decades, anti-angiogenesis has been established as another common approach in cancer treatment because it can effectively inhibit the formation of new blood vessels in tumor tissues and hence restrict the growth, invasion and metastasis of tumor cells. However, the limited efficacy, acquired drug resistance and increased cancer metastasis have become a big clinical challenge for conventional angiogenesis inhibitors. Several strategies have been proposed to overcome these limitations and deficiencies, such as the combination therapy using angiogenesis inhibitors and other cytotoxic drugs with different mechanisms of action, or the development of new anti-angiogenic agents with multiple targets. Notably, natural products provide abundant resources for drug discovery and development due to their diversity, complexity and biocompatibility. The objective of this study was to identify novel angiogenesis inhibitors with multiple targets from natural products, to improve the anti-angiogenic activity of natural products through chemical modification and to develop new combination therapy using natural products and conventional cytotoxic agents for the treatment of different cancers.

In study Ⅰ, we found a natural product named glycyrrhetinic acid, which showed potential anti-ovarian cancer effects in vitro and in vivo, and the underlying anti-cancer mechanisms of glycyrrhetinic acid involved the inhibition of tumor angiogenesis via vascular endothelial growth factor receptor (VEGFR) 2-mediated signaling pathways and the activation of apoptotic pathways in ovarian cancer cells.

In study Ⅱ, we synthesized a new andrographolide derivative named AGS-30 and found that it showed stronger anti-colon cancer effects than andrographolide in vitro and in vivo. Further investigations about the underlying anti-cancer mechanisms of AGS-30 revealed that it could significantly inhibit tumor angiogenesis through VEGFR2-mediated signaling pathways and induce reactive oxygen species-dependent apoptosis in colon cancer cells.

In study Ⅲ, we discovered a natural product named oridonin, which could synergistically enhance the anti-cancer effect of doxorubicin on breast cancer in vitro and in vivo. The underlying mechanisms possibly involved the synergistic inhibition of tumor angiogenesis through VEGFR2-mediated angiogenesis signaling pathways and synergistic pro-apoptotic effects in breast cancer cells. Moreover, we found oridonin could alleviate doxorubicin induced cardiotoxicity in mice model.

In conclusion, by targeting on different mechanisms which are important to the cancer cell growth, it is believed that these compounds may produce promising outcomes in the treatment of cancer and even reduce the sides effects of other chemotherapeutic agents.