Cancer Therapy

Biography

Biography: Kwok-nam Leung

Abstract

Neuroblastoma is the most common extracranial solid tumor found in infancy and childhood and accounts for ~15% of all childhood cancer-related deaths. Naturally-occurring compounds that can inhibit neuroblastoma cell proliferation or trigger them to undergo apoptosis have attracted increasing interest as an alternative therapy for human neuroblatoma. Indirubin-3’-oxime (I3M), an indigo alkaloid, was found to exhibit potent anti-tumor activities on various types of cancer cells. However, its modulatory effects on human neuroblastoma and the underlying mechanisms remain poorly understood. Our results showed that I3M inhibited the growth of the human neuroblastoma LA-N-1, SH-SY5Y and SK-N-DZ cells in a concentration- and time-dependent manner with minimal cytotoxicity on normal cells. Mechanistic studies showed that I3M specifically decreased the expression of mitochondrial regulators ERR and PGC-1 and resulted in decreased mitochondrial mass and mitochondrial membrane potential in LA-N-1 cells. I3M also increased the level of CDK inhibitor p27Kip1 and reduced the levels of CDK2 and cyclin E in LA-N-1 cells, leading to cell cycle arrest at the G0/G1 phase. Studies on the anti-angiogenic activities showed that I3M inhibited the in vitro proliferation, migration, and tube formation of the human microvascular endothelial HMEC-1 cells in a concentration-dependent manner and significantly suppressed the in vivo angiogenesis in Matrigel plugs in mice. Moreover, I3M also down-regulated the expression of Ang-1 and MMP2 genes and up-regulated the expression of Ang-2 gene in HMEC-1 cells. Collectively, our results indicate that I3M might exert its anti-tumor activity by causing mitochondrial dysfunction which led to cell cycle arrest in LA-N-1 cells or through expression of its anti-angiogenic activities. Therefore, I3M might be exploited as a potential therapeutic candidate for the treatment of some forms of human neuroblastomas