Abstract 3122: Combination effect of metformin with gemcitabine for gemcitabine-resistant pancreatic adenocarcinoma

Abstract

Abstract Metformin (MET) is the first-line treatment for type-2 diabetes mellitus. Several epidemiological studies have revealed the anti-cancer effects of metformin, including against pancreatic ductal carcinoma (PDC). Gemcitabine (GEM) has become the standard chemotherapy for PDC but tolerance to GEM is an important issue. We evaluated the anti-tumor effects of MET for GEM-resistant PDC in a xenograft mouse model. For this in vivo study, wild-type BxPC-3 was implanted into both flanks of 7-week-old female BALB/c nude mice. Mice were divided into four groups: (i) control (without any treatment); (ii) GEM-treated group; (iii) MET-treated group; and (iv) combined treatment group (GEM+MET). Mice were fed for 4 weeks. Estimated tumor volumes and body weights were measured each week. Treatments were initiated 2 weeks after implantation. MET (600 mg/kg) was administrated orally every day. GEM (100 mg/kg) was given by intraperitoneal injection every week. The final tumor volumes (in g) were: control, 0.59±0.05; GEM, 0.32±0.07; MET, 0.42±0.08; GEM+MET, 0.23±0.06. The two groups treated with GEM had significantly reduced tumors compared with control, but there were no differences between control and MET groups. The anti-tumor effect of MET for BxG30 (the cell line for GEM-resistant PDC) was evaluated using the method described above. The final tumor volumes were: control, 0.26±0.05; GEM, 0.21±0.05; MET, 0.15±0.06; GEM+MET, 0.11±0.03. Tumor volumes were decreased significantly in GEM+MET groups compared with control. The treated control ratio (T/C%) was calculated: GEM, 80.2%; MET, 54.0%; GEM+MET, 47.2%. The anti-tumor effect of GEM for BxG30 was limited. The MET group showed satisfactory anti-tumor effects, but T/C% was <50% only in the GEM+MET group. This result revealed that combination therapy had excellent anti-tumor effects even for GEM-resistant PDC. The IC50 was 20.25 mM for GEM and 0.004 µg/mL for MET upon single-drug use. Our results showed that MET has a partial anti-tumor effect for PDC. Combination therapy has an excellent effect not only for wild-type PDC but also for GEM-resistant PDC. These data suggest that MET could be used to treat PDC. Citation Format: Keiichi Suzuki, Osamu Takeuchi, Masayoshi Osaku, Yoshinori Yamada. Combination effect of metformin with gemcitabine for gemcitabine-resistant pancreatic adenocarcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3122. doi:10.1158/1538-7445.AM2014-3122