Question

What two types of bio molecules (of the four major classes) show oxidative damage when exposed to the combination of metformin and dichloroacetate when treating breast cancer cells?

Answer 1

Lipid and proteins are two class of biomolecules are get damaged due to oxidative stress. Oxidative stress is critical to the etiology of many “oxidative stress related diseases”, especially neurodegenerative diseases and cancers. Inflammation induces ROS and RNS production via respiratory bursts and inflammatory cytokines, which can activate many oxidant generating enzymes such as inducible nitric oxide synthase (iNOS), cyclooxygenase 2 (COX2), myeloperoxidase (MPO) and eosinophil peroxidase (EPO). Respiratory burst oxidase generates superoxide (O 2• ? ) via the one electron-reduction of oxygen by NADPH, with a secondary production of hydrogen peroxide (H 2 O 2 ), hydroxyl radical (•OH), hypochlorous acid (HOCl), and other activated forms of oxygen [1]. In contrast, RNS including nitric oxide (NO) are generated mainly under inflammatory conditions via the expression of iNOS. NO reacts with O 2• ? to form highly reactive peroxynitrite (ONOO ? ) .Figure 1 shows the general mechanisms of oxidative damage to biomolecules, which results in the dysfunction of the biomolecules and interference with the signaling pathways, leading to oxidative stress-induced diseases. Oxidative damage to lipids causes lipid peroxidation and oxysterol formation, which mainly localize in the cellular membrane resulting in a loss of membrane property. Their reactive end products can consequently damage other molecules. Proteins are mainly functional biomolecules that drive cellular activity. Oxidative damage to proteins may result in protein dysfunction. DNA damage also plays significant roles in not only mutations, but also genetic instability and epigenetic changes. Moreover, many kinds of oncogenes and tumor suppressor genes can be altered by oxidative stress. Therefore, oxidative stress induces disease through the oxidative modification of biomolecules and the alteration of signaling pathways leading to dysregulation of cell cycles, interference with cellular metabolism, genetic instability, epigenetic change and mutation.

Figure 1. Oxidative damage of Lipid and protein molecules.

Both dichloroacetate (DCA) and metformin (Met) have shown promising antitumor efficacy by regulating cancer cell metabolism. However, the DCA-mediated protective autophagy and Met-induced lactate accumulation limit their tumor-killing potential respectively. So overcoming the corresponding shortages will improve their therapeutic effects.

As a mitochondria-targeting agent, DCA can inhibit the activity of pyruvate dehydrogenase kinase (PDK) and subsequently increase the activity of pyruvate dehydrogenase (PDH), which promotes the flux of carbohydrates into mitochondria and thereby enhances aerobic oxidation of glucose. This effect reverses mitochondrial dysfunction and reactivates mitochondria-dependent apoptosis in several tumor cells . Simultaneously, DCA inhibits glycolysis and reduces lactate accumulation, which destroys the acidified tumor microenvironment (The acidified microenvironment is generally in favor of tumor survival) . Although DCA has shown promising prospect in fighting against cancers, it has been reported that DCA induces protective autophagy in colon cancer cells which in turn hinders its apoptotic capacity . So far, it is still unclear whether there is any other apoptosis-associated resistant determinant when DCA refreshes mitochondrial apoptosis.

Met is a traditional drug of first-line therapy for type 2 diabetes. Recent years, increasing evidences indicate that Met can also reduce the risk of cancer in several epidemiological studies. Met suppresses tumor growth through inducing cycle arrest, promoting apoptosis and suppressing autophagy. Furthermore, Met can sensitize some chemotherapeutic drugs such as paclitaxel, erlotinib, etc. More arrestingly, the anti-tumor effect of Met is increasingly linked to the glucose metabolism of cancer. Despite several advantages in clinical trials, Met is hampered for further application because it might lead to lactate accumulation. It is of great interest whether this disadvantage could be overcome by combining other metabolic drugs to make Met more extensively used in chemotherapy. So both Met and DCA will kill breast's cancerous cells by posing effect on the biochemical pathways of cells.