Cisplatin (cDDP) resistance is a matter of concern
in triple-negative breast cancer therapeutics. We measured the
metabolic response of cDDP-sensitive (S) and -resistant (R) MDAMB-231 cells to Pd2Sper Show more
Cisplatin (cDDP) resistance is a matter of concern
in triple-negative breast cancer therapeutics. We measured the
metabolic response of cDDP-sensitive (S) and -resistant (R) MDAMB-231 cells to Pd2Spermine(Spm) (a possible alternative to
cDDP) compared to cDDP to investigate (i) intrinsic response/
resistance mechanisms and (ii) the potential cytotoxic role of
Pd2Spm. Cell extracts were analyzed by untargeted nuclear
magnetic resonance metabolomics, and cell media were analyzed
for particular metabolites. CDDP-exposed S cells experienced
enhanced antioxidant protection and small deviations in the
tricarboxylic acid cycle (TCA), pyrimidine metabolism, and lipid
oxidation (proposed cytotoxicity signature). R cells responded
more strongly to cDDP, suggesting a resistance signature of
activated TCA cycle, altered AMP/ADP/ATP and adenine/uracil fingerprints, and phospholipid biosynthesis (without significant
antioxidant protection). Pd2Spm impacted more markedly on R/S cell metabolisms, inducing similarities to cDDP/S cells (probably
reflecting high cytotoxicity) and strong additional effects indicative of amino acid depletion, membrane degradation, energy/
nucleotide adaptations, and a possible beneficial intracellular γ-aminobutyrate/glutathione-mediated antioxidant mechanism.
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Cancer cells strongly upregulate glucose uptake and glycolysis to produce vital biomolecules for cancer cell survival, proliferation, and metastasis as ATP, lipids, proteins, nucleotides, and lactate. Show more
Cancer cells strongly upregulate glucose uptake and glycolysis to produce vital biomolecules for cancer cell survival, proliferation, and metastasis as ATP, lipids, proteins, nucleotides, and lactate. The Warburg effect is tumours' unique glucose oxidation to give lactate (not pyruvate) even in the presence of oxygen. Nicotinamide adenine dinucleotide (NAD/NADH.H) is used in glycolysis via glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and lactate dehydrogenase (LDH). Both catalyse reversible biochemical reactions to produce 1,3-diphosphoglycerate and lactate, respectively. In this expert opinion and based on published evidence, the author suggests that: "In transformed cells and hyperglycolytic cancer cells, the Warburg effect (permanent conversion of pyruvate to lactate) occurs secondary to a vicious cycle and a closed circuit between GAPDH and LDH (reaction of carcinogenesis) causing increased endogenous oxidative stress and subsequent carcinogenesis. Mitochondrial defects in cancer cells cause hyperglycolysis resulting in NADH.H accumulation (produced during GAPDH step) that obligatorily drives LDH to become an irreversible reaction in the direction of lactate formation (Warburg effect) but not pyruvate formation. Likewise, LDH oxidizes NADH.H producing excessive NAD+ that secondarily drives GAPDH reaction to be irreversible to produce NADH.H and so on. Pyruvate is an antioxidant while lactate is pro-oxidant, causing increased endogenous oxidative stress in cancer cells, tumour's hypoxia and obligatory hyperglycolysis with NADH.H overproduction (GAPDH step) to be consumed in the LDH step for lactate production and NAD+ generation (utilized by GAPDH) and so on". This confirms Warburg's origin of cancer cells. Best anticancer applications based on this hypothesis are: breaking this closed vicious circle using siRNA to target GAPDH and LDH, avoiding strong oxidants (as many cancer chemotherapeutics), and using strong antioxidants for causing antioxidant-oxidant antagonism or antioxidant-lactate antagonism to inhibit the Warburg effect. Strong natural antioxidants of prophetic medicine (related to Prophet Muhammad peace be upon him) such as Zamzam water, Nigella sativa, costus, Ajwa date fruit, olive oil, Al-hijamah and natural honey are strongly recommended to prevent and antagonize the Warburg effect. Show less