Apoptosis inducing activity of hydrazone derivatives of monoterpene indole alkaloids in human colon (HCT116) and liver (HepG2) carcinoma cells

Most chemotherapeutic agents exert their anticancer activity by inducing apoptosis. Therefore, deregulation of apoptotic pathways can confer drug resistance and be a major limiting factor in the effectiveness of anticancer therapy. Several strategies are being employed to address the issue of anticancer drug resistance. One promising approach is the development of effective apoptosis inducers. Tabernaemontana species (Apocynaceae) have been used in traditional medicine to treat cancer. They are able to synthesize a high content and a wide variety of monoterpene indole alkaloids, including iboga-type alkaloids. Previously, we found a significant apoptosis inducing activity for some indole alkaloids from these species [1]. Therefore, to find new apoptosis inducers, the roots of T. elegans, collected in Mozambique, have been investigated. Two monoterpene indole alkaloids of the iboga-type were isolated in large amount from the methanol extract of this plant. In order to obtain a homologous series of bioactive compounds, both isolated monoterpene indole alkaloids were derivatized. Several oximes, hydrazones, semicarbazones, alcohols and esters were obtained. These derivatives were assayed for their ability as apoptosis inducers in HCT116 colon and HepG2 liver cancer cells. Firstly, the cytotoxicity of all compounds was evaluated in both cell lines by the MTS metabolism assay. Out of the tested compounds, two hydrazones displayed significant cytotoxicity in the MTS assay.These compounds were further tested by Guava viacount flow cytometry assays, which indicated that both compounds significantly increased cell death, displaying significantly higher populations of apoptotic cells in both cell lines. Specifically, at 72h of exposure, 10 and 25 mM of these compounds, induced 13 – 30% and over 90% cell death, respectively, in both HCT116 and HepG2 cells.

Acknowledgements: FCT, Portugal (PTDC/QEQ-MED/0905/2012; PhD grantsSFRH/BD/77612/2011 and SFRH/BD/88619/2012).

Keywords: Apoptosis, Apocynaceae, Tabernaemontana, indole alkaloids

References:

[1] Monsoor TA, Ramalho RM, Mulhovo S, Rodrigues CMP, Ferreira MJU. Induction of apoptosis in HuH-7 cancer cells by monoterpene and β-carboline indole alkaloids isolated from the leaves of Tabernaemontana elegans. Bioorg. Med. Chem. Lett. 2009; 19: 4255 – 4258