Inositol Glycans and Cancer
For cancer to progress as a disease, rapidly dividing tumor cells must evade a natural control mechanism that would normally kill rapidly dividing cells by inducing them to engage in apoptosis or programmed cell death. One way that cancer cells escape intrinsic apoptosis, usually triggered by mitochondrial excess, is by switching from aerobic to anaerobic metabolism, even in the presence of oxygen. By changing their metabolism, a phenomenon known as the Warburg Effect,1 cancer cells decrease the stress on their mitochondria and avoid triggering intrinsic apoptosis.
In collaboration with Prof. Susumu Suzuki of Tohoku University, we are engaged in a project to design small molecules that have the property that they stimulate aerobic metabolism and activate mitochondria. In particular, we are designing small lipid-linked inositol glycans (IGs) to stimulate metabolism more effectively than other small IGs, as shown schematically above. Such molecules may be able to reverse the Warburg Effect and restore intrinsic apoptosis in cancer cells, thereby killing them. Since most normal cells are already engaged in aerobic metabolism, it is hoped that these molecules will not affect them. If successful, this would provide a new strategy for the treatment of cancer.
We have synthesized the first molecule in this class and preliminary results with cultured cancer and normal cells are promising, showing selective toxicity toward the cancer cells.2 We are now engaged in studying the biochemical mechanism of this effect.
(1) Kroemer, G. Oncogene, 2006, 25, 4630-4632.
(2) Azev, V. N., Suzuki, S., Chakraborty, N. and d'Alarcao, M. 2015, In preparation.