Cancer cells are known to have altered bioenergetics. Otto Warburg (Warburg, 1956) detected that cancer cells can elevate glycolysis in favour of mitochondrial respiration, making them better suited to cope with hypoxic conditions in solid tumours. We and others have recently shown that elevated glycolysis can make cancer cell resistant to therapeutically induced bioenergetic crisis (Elstrom et al., 2004; Huber et al., 2011a; Plas et al., 2001). To date, the cause of this “Warburg effect” is unknown. Some evidences point to over-expression of glycolytic enzymes, while other findings suggest oncogenic alterations of pro-survival signalling such as PI3K/AKT or the ERK pathway (Plas et al., 2001).
To investigate resistance of cancer cells to therapeutically induced cell death, it is therefore necessary to better understand the cause of oncogenic elevation of glycolysis.
In turn, existing and prospective chemotherapeutic drugs not only induce apoptosis or necrosis, but also influence cellular and mitochondrial bioenergetics, and pro-survival pathways. The receptor tyrosine kinase inhibitor and chemotherapeutic cetuximab can deactivate the pro-survival PI3K /AKT pathway. The pro-apoptotic BCL2 protein mimetic gossypol, which is in clinical trial colorectal cancer, is also known to inhibit lactate dehydrogenase, a key enzyme in cellular bioenergetics.
A systems approach is therefore best suited to simultaneously characterise and assess the influence of existing and putative chemotherapeutics on cellular bioenergetics, pro-survival and cell death pathways.