We showed here that cigarette smoke condensate vapor can induce cisplatin resistance. We also found that the expression of AK3 is affected by CSC vapor and that restoration of this gene sensitizes the cells to cisplatin. Secondhand smoke exposure or exposure to environmental smoke has been assessed as a risk of bladder cancer. Our approach here is based on recent studies on normal oral keratinocytes indicating that exposure of cells to vapor component of cigarette smoke extract is as effective as direct treatment of cigarette smoke extract. These studies also indicated that chronic exposure to cigarette smoke provide a better model in vivo than acute exposure to cigarette smoke. Studies with environmental cigarette smoke or secondhand smoke in mice have demonstrated a variety of early alterations, including cytogenetic damage in bone marrow and peripheral blood, formation of lipid peroxidation products in lung, increase of bulky DNA adducts and oxidatively generated DNA damage. Our observation in this model that AK3 protein expression is decreased by CSC vapor builds on an old observation that cigarette smoke poisons lung cilia through a direct effect on adenylate kinases. Also increase of AK3 mRNA level and AK3 enzyme activity were previously observed in rat skeletal muscle. In addition, AK3 protein was found to increase 10-fold during neural differentiation of P19 embryonal carcinoma cells. The induction of AK3 mRNA was also shown in response to hypoxia in HeLa cells depending on the presence of hypoxiainducible factor-1. Here we show a direct effect on cancer cells and provide novel evidence that decreased expression of AK3 in the presence of CSC vapor is accompanied with decreased sensitivity of bladder cells to cisplatin and restoration of AK3 sensitizes cells to cisplatin. By linking AK3, our data support the notion that mitochondria plays an important role in cigarette smoke induced cisplatin resistance. Studies indicate that components present in cigarette smoke extract are able to pass through the membranes of mitochondria. Further it has been proven that highly reactive components like polycyclic aromatic SCH 202676 hydrobromide hydrocarbons, aldehydes, phenols, heavy metals, and amines are lipophilic candidates that easily enter the cell and disturb mitochondria. AK3 is present in the mitochondrial matrix and probably SR 48692 functions in transferring the high-energy phosphate to AMP from GTP that is synthesized by the TCA cycle.