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Hypothalamic digoxin mediated model for oncogenesis
1Dept. of Neurology, Medical College Hospital, Trivandrum, Kerala, India.
Abstract:
This study assessed the changes in the isoprenoid pathway and its metabolites digoxin, dolichol and ubiquinone in neoplasms (CNS astrocytomas - glioblastoma multiforme and high grade non - Hodgkin's lymphoma). The following parameters were assessed-isoprenoid pathway metabolites, tyrosine and tryptophan catabolites, glycoconjugate metabolism, RBC membrane composition and free radical metabolism. There was an elevation in plasma HMG CoA reductase activity, serum digoxin and dolichol and a reduction in RBC membrane Na+-K+ ATPase activity, serum ubiquinone and magnesium levels. Serum tryptophan, serotonin, nicotine and quinolinic acid were elevated while tyrosine, dopamine, noradrenaline and morphine were decreased. The total serum glycosaminoglycans and glycosaminoglycan fractions (except dermatan sulphate in the case of CNS astrocytomas), the activity of GAG degrading enzymes and glycohydrolases, carbohydrate residues of glycoproteins and serum glycolipids were elevated. HDL cholesterol showed a significant decrease and free fatty acids & triglycerides were increased. The RBC membrane glycosaminoglycans, hexose and fucose residues of glycoproteins and phospholipids were reduced. The activity of all free radical scavenging enzymes, concentration of glutathione, iron binding capacity and ceruloplasmin decreased significantly while the concentration of malondialdehyde (MDA), hydroperoxides, conjugated dienes and NO increased. The concentration of alpha tocopherol was unaltered. Membrane Na+-K+ ATPase inhibition due to elevated digoxin, altered membrane structure and digoxin related tyrosine / tryptophan transport defect leading to increased levels of depolarising tryptophan catabolites and decreased levels of hyperpolarising tyrosine catabolites can lead to alteration in intracellular calcium/magnesium ratios and oncogene activation. Intracellular magnesium deficiency can produce defective microtubule related spindle fibre dysfunction and chromosomal non-dysjunction contributing to neoplastic cellular polyploidy and aneuploidy. Digoxin induced tryptophan/tyrosine transport defect can alter neurotransmitter patterns with increased serotonin, quinolinic acid, nicotine & glutamatergic transmission and reduced dopamine, morphine and noradrenaline levels leading to oncogenesis. Glycoconjugate metabolism is altered by elevated dolichol levels and magnesium depletion consequent to Na+-K+ ATPase inhibition. There is a qualitative alteration in proteoglycans and glycoproteins, defective membrane formation and structure and reduced lysosomal stability leading to disordered contact inhibition and tumour antigen presentation contributing to oncogenesis. Digoxin induced alteration in intracellular calcium/magnesium ratios and low ubiquinone levels can lead to a mitochondrial dysfunction resulting in increased free radical generation and reduced scavenging & caspase-3 activation producing a P21 defect contributing to oncogenesis.
Insights
This study reveals altered isoprenoid metabolism, neurotransmitter patterns, and membrane integrity in brain and lymphoma cancers. These changes, including elevated digoxin and dolichol, contribute to oncogenesis through various cellular dysfunctions.
Area of Science:
- Biochemistry
- Oncology
- Cell Biology
Background:
- Neoplasms exhibit complex metabolic alterations.
- The isoprenoid pathway and its metabolites play crucial roles in cellular processes.
- Understanding these changes is vital for cancer research.
Purpose of the Study:
- To investigate alterations in the isoprenoid pathway and related metabolites in CNS astrocytomas and non-Hodgkin's lymphoma.
- To assess associated changes in tyrosine and tryptophan catabolites, glycoconjugate metabolism, RBC membrane composition, and free radical metabolism.
- To elucidate the mechanisms linking these metabolic shifts to oncogenesis.
Main Methods:
- Assessed isoprenoid pathway metabolites (digoxin, dolichol, ubiquinone).
- Analyzed tyrosine and tryptophan catabolites, glycoconjugate metabolism, RBC membrane composition, and free radical metabolism.
- Measured enzyme activities, metabolite concentrations, and membrane component levels in cancer patients and controls.
Main Results:
- Elevated plasma HMG CoA reductase, serum digoxin, and dolichol.
- Reduced RBC membrane Na+-K+ ATPase activity, serum ubiquinone, and magnesium levels.
- Altered tryptophan/tyrosine catabolites, increased glycosaminoglycans, elevated free radicals (MDA, hydroperoxides), and decreased scavenging enzymes.
- Decreased HDL cholesterol, increased FFAs and triglycerides.
Conclusions:
- Elevated digoxin and altered membrane function contribute to oncogenesis via ion imbalance and transport defects.
- Magnesium deficiency impacts microtubule function and chromosomal stability, promoting aneuploidy.
- Metabolic shifts, including altered neurotransmitter patterns and glycoconjugate metabolism, drive neoplastic progression.
- Mitochondrial dysfunction and increased oxidative stress, exacerbated by low ubiquinone, further promote cancer development.