Chemotherapeutic properties of phospho-nonsteroidal anti-inflammatory drugs, a new class of anticancer compounds.
Nonsteroidal anti-inflammatory drugs (NSAID) exhibit antineoplastic properties, but conventional NSAIDs do not fully meet safety and efficacy criteria for use as anticancer agents. In this study, we evaluated the chemotherapeutic efficacy of 5 novel phospho-NSAIDs, each of which includes in addition to the NSAID moiety a diethylphosphate linked through a butane moiety. All 5 compounds inhibited the growth of human breast, colon, and pancreatic cancer cell lines with micromolar potency. In vivo investigations confirmed the antitumor activity of phospho-aspirin (PA) and phospho-sulindac (PS) in inhibiting tumor growth in established human xenograft models, in which cell proliferation was suppressed and apoptosis enhanced in the absence of detectable animal toxicity. Notably, all of the phospho-NSAIDs tested induced reactive oxygen and nitrogen species in cultured cells, with PA and PS inducing detectable levels of oxidative stress in vivo that were associated positively with apoptosis and negatively with proliferation. Potentially explaining these effects, all of the phospho-NSAIDs tested also inhibited the thioredoxin system and the redox sensitive transcription factor NF-κB. Taken together, our findings show the strong anticancer efficacy and promising safety of phospho-NSAIDs in preclinical models of breast, colon, and pancreatic cancer, suggesting further evaluation as anticancer agents.
Department of Medicine, Division of Cancer Prevention, Stony Brook University, Stony Brook, New York 11794, USA.
Liqun
L
Huang
Gerardo G
GG
Mackenzie
Yu
Y
Sun
Nengtai
N
Ouyang
Gang
G
Xie
Kvetoslava
K
Vrankova
Despina
D
Komninou
Basil
B
Rigas
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001241:Aspirin / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005260:Female; D019073:HT29 Cells; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D015394:Molecular Structure; D016328:NF-kappa B / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010755:Organophosphates / Q000737:chemistry; D013467:Sulindac / Q000737:chemistry / Q000494:pharmacology; D013880:Thioredoxin-Disulfide Reductase / Q000378:metabolism; D013879:Thioredoxins / Q000378:metabolism; D013997:Time Factors; D023041:Xenograft Model Antitumor Assays
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016328:NF-kappa B; D010755:Organophosphates; D013467:Sulindac; D013879:Thioredoxins; C034789:diethyl phosphate; D013880:Thioredoxin-Disulfide Reductase; D001241:Aspirin