Seminars

Currently, there are no approved anti-cancer drugs from Malaysia despite her abundance of natural resources. There are initiatives on potential drugs, such as, tocotrienol from oil palm and silvestrol from a rainforest tree. In the Cancer Research Lab’s efforts to contribute, chemical investigations of the Malaysian ethno-medicinal Zingiberaceae plant Alpinia conchigera and isolation of the active compound,1'S-1'-acetoxychavicol acetate (ACA), initiated the study. This presentation is a summary of work carried out on ACA from 2006 until present. It involved 9 PhD (5 graduated) and 1 MSc (graduated) students, with currently 14 papers published and 1 patent filed. These projects look at the potential of ACA to be used as anti-cancer drug against human cancers. ACA was found to induce apoptotic cell death, cause cell cycle arrest at the G0/G1 phase, and suppress migration most effectively in oral squamous cell carcinoma, by regulating the NF-κB signalling pathway. It displayed better effects in lung and prostate tumours when conjugated with recombinant human alphafetoprotein. The acute and sub-acute toxicity profiles of ACA were also unfolded while quantification of ACA using liquid chromatography quadrupole time-of-flight mass spectrometer (QTOF-LCMS) in the rat plasma samples from the toxicity study is currently under investigation. The interactions of ACA with the cytochrome P450 superfamily metabolising enzymes was investigated to identify the CYP enzymes involved. This is to facilitate the understanding of drug-drug interactions when ACA is co-administered with other therapeutic drugs. When combined with the immune-potentiating bacteria, Mycobacterium indicus pranii, they synergistically chemo-sensitise and eradicate targeted breast malignancies. Lipid-based ACA nanoparticles are also being investigated to enable improved delivery to cancer cells while protecting the drug from degradation in the biological environment. In addition, autophagy-inducing ability of ACA in human lung cancer was examined. The  modification of miRNA expression by ACA to mediate its anti-cancer effects was also elucidated. In a study to search for analogues of ACA with increased anti-cancer properties, nine analogues of ACA were hemi-synthesized and their anti-cancer properties analysed. Since ACA is able to inhibit the activation of NF-κB, it is important to investigate if ACA and analogues have the ability to degrade or inhibit the degradation of target proteins via the ubiquitin proteasome system and be useful as a proteasome inhibitor. This was investigated in an in silico docking analysis of possible binding sites of the compounds with proteasome and verified in the 26S proteasome analysis in breast cancer cells. In the UM/NAIST collaborative study, the interaction between ACA and inflammatory activity is hoped to provide a new insight into the role of ACA in cancer immunity. In conclusion, the research has characterised ACA and paved the way to be further developed clinically in order to be used in combination with FDA drugs, mycobacterium, and lipid-carrier for better therapeutic potential, and has pioneered the basis for future combination of anti-cancer drugs developments.