Penicillamine as a potent protector against injurious effects of cigarette smoke in aerodigestive tract cancer.
BACKGROUND
Cigarette smoke (CS) is the major risk factor for aerodigestive tract cancers such as lung and oral cancers.


METHODS
In in vitro models of lung and oral cancers, we found D-penicillamine (PenA) to be a most potent protector against CS, both in the absence and presence of saliva (a highly pro-oxidative condition).


RESULTS
The survival rate of lung cancer cells and oral cancer cells was reduced by CS in the absence of saliva by 39-45% (p < 0.01) and by 55-60% (p < 0.01) in the presence of saliva. The addition of 5 mM PenA to cell medium prior to CS exposure limited cell loss to 22-25% only (p < 0.01). Similarly, the iron chelator desferal protected the cells only in the presence of saliva. PenA also protected against a CS-induced increase in carbonyls (oxidized proteins) and decrease in p53 levels (in the presence of saliva) and mitochondrial membrane potential (a hallmark of CS-induced apoptotic cell death). Malfunctioning p53 often characterizes carcinogenesis of CS-induced cancers.


CONCLUSIONS
Redox-active iron and copper in pleural fluid and saliva, upon encounter with CS, may be responsible for this carcinogenesis, mediated via alteration of p53 function. Chelation of redox-active metals may be an efficient tool for prevention of CS-induced lung and oral cancers. The superiority of PenA results from its copper-chelating action as well as its antialdehyde and anti-inflammatory capabilities.
Nagler
Rafael
R
Department of Molecular Pharmacology, Rappaport Family Institute for Research in the Medical Sciences, Technion-Israel Institute of Technology, Haifa 31096, Israel. nagler@tx.technion.ac.il
Cohen
Shiri
S
Savulescu
Dana
D
Leschiner
Svetlana
S
Otradnov
Irina
I
Gavish
Moshe
M
D016588:Anticarcinogenic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D009062:Mouth Neoplasms / Q000188:drug therapy*; D010396:Penicillamine / Q000494:pharmacology* / Q000627:therapeutic use; D012463:Saliva; D012906:Smoke / Q000009:adverse effects*; D012907:Smoking / Q000009:adverse effects*
D016588:Anticarcinogenic Agents; D012906:Smoke; D010396:Penicillamine