Question

A hypothetical cancer drug has been shown to prevent electrons from coupling with O2 at the end of the electron transport chain of cellular respiration. in early trials, test subjects were shown to have large amounts of lactic acid in their blood complained of fatigue. Discuss how this drug's mode of action might lead to these two side effects

Answer 1

ANSWER

(1)

Byproducts of normal mitochondrial metabolism and homeostasis include the buildup of potentially damaging levels of reactive oxygen species (ROS), Ca2+, etc., which must be normalized. Evidence suggests that brief mitochondrial permeability transition pore (mPTP) openings play an important physiological role maintaining healthy mitochondria homeostasis. Adaptive and maladaptive responses to redox stress may involve mitochondrial channels such as mPTP and inner membrane anion channel (IMAC). Their activation causes intra- and intermitochondrial redox-environment changes leading to ROS release. This regenerative cycle of mitochondrial ROS formation and release was named ROS-induced ROS release (RIRR). Brief, reversible mPTP opening-associated ROS release apparently constitutes an adaptive housekeeping function by the timely release from mitochondria of accumulated potentially toxic levels of ROS (and Ca2+). At higher ROS levels, longer mPTP openings may release a ROS burst leading to destruction of mitochondria, and if propagated from mitochondrion to mitochondrion, of the cell itself. The destructive function of RIRR may serve a physiological role by removal of unwanted cells or damaged mitochondria, or cause the pathological elimination of vital and essential mitochondria and cells. The adaptive release of sufficient ROS into the vicinity of mitochondria may also activate local pools of redox-sensitive enzymes involved in protective signaling pathways that limit ischemic damage to mitochondria and cells in that area. Maladaptive mPTP- or IMAC-related RIRR may also be playing a role in aging. Because the mechanism of mitochondrial RIRR highlights the central role of mitochondria-formed ROS, we discuss all of the known ROS-producing sites (shown in vitro) and their relevance to the mitochondrial ROS production in vivo.

Hypoxia-Inducible Factor

Oxygen sensing in cells is provided by multiple mechanisms, among which central mechanism lies in action of 2OG-dependent prolyl hydroxylases (PHDs), alternatively termed Egl nine homolog 1 proteins (EGLN) . PHDs provide a ferrous iron- (FeII-) dependent plus O2-dependent plus 2-oxoglutarate-dependent hydroxylation of HIF-1α (or HIF-2α which is constantly degraded. Therefore, by decreased O2, by lowering the other PHD co-factors and by the increased ROS, PHDs are also inhibited and hence the HIF system is activated [20] (Figure 3). The system is more complex, since also factor inhibiting HIF (FIH) hydroxylates HIFα, but at different sites. Both, PHD and FIH are affected by ROS, hence participate in redox signaling.

(2)

Targeting common weaknesses of cancer is an important strategy for cancer therapy. Glucose is a nutrient that maintains essential cellular metabolism, supporting cancer cell survival, growth and proliferation. Depriving glucose rapidly kills cancer cells. Most cancer cells possess a feature called Warburg effect, which refers to that cancer cells even with ample oxygen exhibit an exceptionally high glycolysis rate and convert most incoming glucose to lactate. Although it is recognized that Warburg effect confers growth advantage to cancer cells when glucose supply is sufficient, this feature could be considered as a fatal weakness of cancer cells when glucose supply is a problem. As glucose supply in many solid tumors is poor, and as most cancer cells have exceptionally high glycolytic capacity, maximizing cancer cell glycolysis rate would possibly exhaust intratumoral glucose, leading cancer cell to death. Lactate and proton are two common factors in solid tumors, they jointly protect cancer cells against glucose deprivation, and they are also powerful regulators dictating glucose metabolic phenotypes of cancer cells. Disrupting the joint action of lactate and proton, for example, by means of bicarbonate infusion into tumor, could maximize cancer cell glycolytic rate to rapidly use up glucose, expose their vulnerability to glucose deprivation and ultimately kill cancer cells. A pilot clinical study demonstrated that this approach achieved a remarkable improvement in local control of large and huge hepatocellular carcinoma.

Warburg effect Cytokines Í Lactate Lactate Pathogen Normal cell Inflammed cell Transformed cell

Hypothetical mechanism of inflammation-induced cancer feeding. The cytokines are released by infected cells and induce the Warburg effect in a different subpopulation, the lactate secreted would be used by transformed cells for anabolic and catabolic processes