Abstract #5529: Multidrug resistance in small cell lung cancer cell lines

Lung cancer is the leading cause of cancer death. Small cell lung cancer (SCLC) is the most aggressive form of lung cancer that does not respond well to surgery alone or radiotherapy alone. The standard treatment of SCLC is the administration of anticancer drugs, such as cisplatin and etoposide, along with thoracic radiotherapy. Although there is a good initial response to chemotherapy, most SCLC patients develop multidrug resistance (MDR) that is responsible for relapse. Thus, virtually no curative treatment for SCLC exists so far, leading to a 5-year survival rate of less than 5%. Since development of MDR in SCLC patients is responsible for chemotherapeutic treatment failure, understanding the mechanisms of MDR in SCLC is an important step to treat the SCLC patients. In order to achieve this goal, two SCLC cell lines, H69 and H69AR, were used to elucidate the molecular mechanisms of MDR in these cells. H69 is a drug sensitive SCLC cell line derived from an SCLC patient. Upon stepwise treatment with increasing concentration of doxorubicin, the surviving cells, termed H69AR, are resistant to many anti-cancer drugs, providing a great opportunity to study the mechanisms of MDR in SCLC cells. We have found that 27 out of 84 genes potentially involved in MDR, including MRP1 and Bcl2, out of 84 genes potentially involved in MDR were over-expressed in H69AR cell, comparing to H69 cell. All of these 27 factors may contribute to the MDR in H69AR cell. Interestingly, treatment of H69AR cell with Bcl2/RNAi not only knocked-down the expression of Bcl2 but also MRP1, resulting in the Bcl2/RNAi treated H69AR cells being more sensitive to anticancer drugs than the parental H69AR cell. Whether the Bcl2/RNAi-treatment will also knock-down the expressions of other MDR-related genes is not known yet and will be determined. If a factor, for example, EGFR or GSTP1, is still over-expressed in these Bcl2/RNAi-treated H69AR cells, their specific inhibitors, such as gefitinib or ethacrynic acid, will be utilized along with anticancer drugs such as cisplatin and etoposide. One way or another, we will attempt to overcome the drug resistance in this SCLC MDR cancer cell line. Insights gained from these studies may provide a novel approach to combat MDR in SCLC patients. Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 5529.