From Warburg effect to Reverse Warburg effect; the new horizons of anti-cancer therapy

An old ideology of killing the cancer cells by starving them is the underlying concept of the Warburg effect. It is the process of aerobic glycolysis exhibited by the cancer cells irrespective of anaerobic glycolysis or mitochondrial oxidative phosphorylation following by their healthy counterparts. Dr Otto Heinrich Warburg proposed this abnormal metabolic behaviour of tumour cells in 1920. This phenomenon illustrates the metabolic switching in tumour cells from oxidative phosphorylation to aerobic glycolysis triggered by an injury to the mitochondrial respiration. A modernised perspective of the Warburg hypothesis termed the Reverse Warburg effect introduced in 2009, with a two-compartment model describing the metabolic symbiosis between cancer cells and its neighbouring stromal cells or cancer-associated fibroblasts. This theory is elucidating the aerobic glycolysis occurring in cancer-associated fibroblasts which leads to the generation and deposition of the lactate in tumour microenvironment along with its significance. The transportation of lactate to and from the cancer cell and extracellular space is facilitated by the lactate transporters called monocarboxylate transporters. This lactate generated irrespective of the hypoxic or aerobic conditions acts as a primary metabolic fuel for the cancer cells. Besides, it will create a tumour microenvironment that is favouring the progression and metastasis of malignancy through several means. Overall, the lactate produced through this metabolic reprogramming is supporting and worsening the conditions of cancer. The concept of the Reverse Warburg effect proposes a new anti-cancer treatment modality by preventing the generation and transport of lactate through the inhibition of monocarboxylate transporters and in turn, defeating the cancer disease by arresting the cancer cells along with silencing tumour microenvironment.