Also see:
Lactate vs. CO2 in wounds, sickness, and aging; the other approach to cancer
Altitude Sickness: Therapeutic Effects of Acetazolamide and Carbon Dioxide
Comparison: Carbon Dioxide v. Lactic Acid
Carbon Dioxide Basics
Comparison: Oxidative Metabolism v. Glycolytic Metabolic
Promoters of Efficient v. Inefficient Metabolism
Altitude Sickness: Therapeutic Effects of Acetazolamide and Carbon Dioxide
Low CO2 in Hypothyroidism
Protective Altitude
Lactate Paradox: High Altitude and Exercise
Altitude Improves T3 Levels
Protective Carbon Dioxide, Exercise, and Performance
Synergistic Effect of Creatine and Baking Soda on Performance
Ray Peat, PhD on Carbon Dioxide, Longevity, and Regeneration
Mitochondria & Mortality
Altitude and Mortality
Drugs similar to acetazolamide, sulfonamides that inhibit carbonic anhydrase, have recently been discovered to stop the growth of a wide variety of tumors. -Ray Peat, PhD
Lactic acid and carbon dioxide oppose each other. Cancer patients have a deficiency of carbon dioxide because of the respiratory defect where lactic acid is formed from glucose despite the presence of oxygen (Warburg effect/aerobic glycolysis). Carbonic anhydrase inhibitors cause the body to retain carbon dioxide. Those living at high altitude retain more carbon dioxide (Haldane-Bohr Effect) and have less susceptibility to degenerative disease, including cancer. High altitude itself acts naturally like carbonic anhydrase inhibitor therapy.
Bioorg Med Chem. 2001 Mar;9(3):703-14.
Carbonic anhydrase inhibitors: sulfonamides as antitumor agents?
Supuran CT, Briganti F, Tilli S, Chegwidden WR, Scozzafava A.
Novel sulfonamide inhibitors of the zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1) were prepared by reaction of aromatic or heterocyclic sulfonamides containing amino, imino, or hydrazino moieties with N,N-dialkyldithiocarbamates in the presence of oxidizing agents (sodium hypochlorite or iodine). The N,N-dialkylthiocarbamylsulfenamido-sulfonamides synthesized in this way behaved as strong inhibitors of human CA I and CA II (hCA I and hCA II) and bovine CA IV (bCA IV). For the most active compounds, inhibition constants ranged from 10(-8) to 10(-9) M (for isozymes II and IV). Three of the derivatives belonging to this new class of CA inhibitors were also tested as inhibitors of tumor cell growth in vitro. These sulfonamides showed potent inhibition of growth against several leukemia, non-small cell lung, ovarian, melanoma, colon, CNS, renal, prostate and breast cancer cell lines. With several cell lines. GI50 values of 10-75 nM were observed. The mechanism of antitumor action with the new sulfonamides reported here remains obscure, but may involve inhibition of CA isozymes which predominate in tumor cell membranes (CA IX and CA XII), perhaps causing acidification of the intercellular milieu, or inhibition of intracellular isozymes which provide bicarbonate for the synthesis of nucleotides and other essential cell components (CA II and CA V). Optimization of these derivatives from the SAR point of view, might lead to the development of effective novel types of anticancer agents.
J Enzyme Inhib. 2000;15(6):597-610.
Carbonic anhydrase inhibitors: aromatic sulfonamides and disulfonamides act as efficient tumor growth inhibitors.
Supuran CT, Scozzafava A.
Aromatic/heterocyclic sulfonamides generally act as strong inhibitors of the zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1). Here we report the unexpected finding that potent aromatic sulfonamide inhibitors of CA, possessing inhibition constants in the range of 10(-8)-10(-9) M (against all the isozymes), also act as efficient in vitro tumor cell growth inhibitors, with GI50 (molarity of inhibitor producing a 50% inhibition of tumor cell growth) values of 10 nM-35 microM against several leukemia, non-small cell lung cancer, ovarian, melanoma, colon, CNS, renal, prostate and breast cancer cell lines. The investigated compounds were sulfanilyl-sulfanilamide-, 4-thioureido-benzenesulfonamide- and benzene-1,3-disulfonamide-derivatives. The mechanism of antitumor action with these sulfonamides is unknown, but it might involve either inhibition of several CA isozymes (such as CA IX, CA XII, CA XIV) predominantly present in tumor cells, a reduced provision of bicarbonate for the nucleotide synthesis (mediated by carbamoyl phosphate synthetase II), the acidification of the intracellular milieu as a consequence of CA inhibition or uncoupling of mitochondria and potent CA V inhibition among others. A combination of several such mechanisms is also plausible. Optimization of such derivatives from the SAR point of view, might lead to the development of effective novel types of anticancer agents/therapies.
Eur J Med Chem. 2000 Sep;35(9):867-74.
Carbonic anhydrase inhibitors–Part 94. 1,3,4-thiadiazole-2-sulfonamidederivatives as antitumor agents?
Supuran CT, Scozzafava A.
Potent sulfonamide inhibitors of the zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1), derivatives of I ,3,4-thiadiazole-2-sulfonamide, possessing inhibition constants in the range of 10(-8)-10(-9) M against isozymes II and IV, were shown to act as efficient in vitro tumour cell growth inhibitors with GI(50) (molarity of inhibitor producing a 50% inhibition of tumour cell growth) values typically in the range of 0.1-30 microM against several leukaemia, non-small cell lung cancer, ovarian, melanoma, colon, CNS, renal, prostate and breast cancer cell lines. The mechanism of antitumour action with the new sulfonamides reported here is unknown, but it might involve either inhibition of several CA isozymes (such as CA IX, CA XII, CA XIV) present predominantly in tumour cell membranes, acidification of the intracellular environment as a consequence of CA inhibition, uncoupling of mitochondria and/or strong CA V inhibition, or a combination of several such mechanisms. Such derivatives might lead to the development of effective novel types of anticancer agents/therapies.
