Multidrug resistance (MDR) is a major impediment to successful chemotherapy for lung cancer. Overexpression of multidrug resistance-associated protein 1 (MRP1) appears to be involved in MDR development in lung cancer cells. A number of chemotherapeutic agents including doxorubicin (DOX) were reported to induce MRP1 expression in human lung cancer cells. In our study, we investigated the mechanism by which DOX induces MRP1 expression in human small cell lung cancer (SCLC) cell lines, GLC4 and NCI-H82. These cells expressed MRP1 protein at low levels and were sensitive to DOX. Doxorubicin at 50 nM induced a marked increase in MRP1 expression in 24 hr, and stimulated c-jun N-terminal kinase (JNK) activity. Treatment with a JNK inhibitor, SP600125, significantly inhibited MRP1 induction. Furthermore, transfection with JNK1 and JNK2 antisense oligonucleotides markedly inhibited DOX-induced MRP1 expression. Chromatin immunoprecipitation assays revealed an enhanced recruitment of phosphorylated c-jun to the MRP1 promoter containing the AP-1 site upon DOX stimulation, which was inhibited by pretreatment with SP600125. Surprisingly, GLC4 cells exposed to DOX for 24 hr maintained increased MRP1 expression and resistance to DOX for at least 3 weeks. Pretreatment with SP600125 before DOX stimulation blocked the appearance of the MDR phenotype as well as MRP1 induction in GLC4 cells. These findings suggest that JNK activation may play an essential role for the induction of MRP1 protein in human SCLC cells by chemotherapeutic agents and that combined treatment of a JNK inhibitor with anticancer drugs may prevent the development of MDR by the abrogation of MRP1 induction. ' 2005 Wiley-Liss, Inc.Key words: MRP1; JNK; doxorubicin; small-cell lung cancer; multidrug resistance Small cell lung cancer (SCLC) accounts for 15-25% of all lung cancer patients.1,2 Although up to 90% of SCLC tumors initially respond to chemotherapy, patients with SCLC often relapse with multidrug resistant state. There are several types of multidrug resistance (MDR) to anticancer agents, and some of them were identified in human carcinoma cell lines in vitro. One of the mechanisms of MDR is decreased accumulation of drug within cells because of reduced inward transport or increased drug efflux, such as overexpression of adenosine triphosphate (ATP)-binding cassette (ABC) transporters. 3 P-glycoprotein (P-gp) that was cloned from KB-C 2.5 cells was the first ABC transporter identified. 4 Overexpression of P-gp has been detected in many multidrug resistant tumor cell lines and a variety of tumors from patients with both acquired and inherent drug resistance.5 Although P-gp is implicated in drug resistance in a number of tumor types, it is infrequently expressed in lung cancer cells. Another ABC transporter was cloned from the doxorubicin (DOX) resistant H69/AR SCLC cell line by Cole et al. 6 The transporter was designated as multidrug resistance-associated protein 1 (MRP1). The MRP family is now composed of 9 related ABC transporters that are able to transp...

Ionizing radiation (IR) is known to upregulate cell surface Fas through p53 activation in various cells. However, the signaling pathway intermediating between p53 activation and cell surface Fas upregulation remains to be elucidated. Recently, Fas-associated phosphatase-1 (FAP-1) has been reported to associate with Fas and inhibit cell surface Fas expression. We evaluated the expression of FAP-1 mRNA following IR in A549 cells. Ionizing radiation inhibited the expression of FAP-1 mRNA. Pretreatment with p53 inhibitor pifithrin a cancelled the IR-induced downregulation of FAP-1 mRNA. These results suggest that IR-induced p53 activation may upregulate cell surface Fas via the down-modulation of FAP-1.

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We present a case of thymic carcinoid, in which primary and metastatic lesions of lymph nodes and bones could be detected by [(18)F]fluoro-2-deoxy-D-glucose (FDG)-PET, but not by (123)I-meta-iodobenzylguanidine ((123)I-MIBG) SPECT, or by (99m)Tc-methylene diphosphonate ((99m)Tc-MDP) bone scintigraphy. FDG-PET may be a useful tool for managing thymic carcinoids in patients with negative results on (123)I-MIBG SPECT or (99m)Tc-MDP imaging.