Oxidative stress therapy for solid tumors - a proposal.
Many cancers are deficient in catalase activity, and maintain a moderate level of oxidative stress to aid their proliferation and survival. It may prove feasible to achieve substantial selective tumor kill with a three-pronged strategy for acutely exacerbating oxidative stress in cancer cells: inducing increased production of oxidants in tumors with sustained high-dose infusions of sodium ascorbate and menadione, while concurrently undercutting the antioxidant defenses of cancer cells by imposing glucose deprivation - as with 2-deoxyglucose administration or a hypoglycemic insulin clamp - and by suppressing hypoxia-inducible factor-1 activity with available agents such as salicylate, rapamycin, and irinotecan. Inhibition of pyruvate dehydrogenase-1 with dichloroacetate may also promote oxidative stress in hypoxic cancer cells. Cell culture studies could be employed to devise effective protocols that could be tested in xenografted rodents and, ultimately, in exploratory clinical trials.
McCarty
Mark F
MF
Oasis of Hope Hospital, Playas de Tijuana, Tijuana, B.C. 22504, Mexico. mccarty@pantox.com
Barroso-Aranda
Jorge
J
Contreras
Francisco
F
D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001205:Ascorbic Acid / Q000627:therapeutic use; D002374:Catalase / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000037:antagonists & inhibitors; D008954:Models, Biological; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D024483:Vitamin K 3 / Q000627:therapeutic use
D000975:Antioxidants; D051793:Hypoxia-Inducible Factor 1; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D024483:Vitamin K 3; D002374:Catalase; D017346:Protein Serine-Threonine Kinases; D005947:Glucose; D001205:Ascorbic Acid