Suppression of pancreatic tumor growth by combination chemotherapy with sulindac and LC-1 is associated with cyclin D1 inhibitionin vivo

Abstract

The design of novel targeted or combination therapies may improve treatment options for pancreatic cancer. Two targets of recent interest are nuclear factor-KB (NF-KB) and cyclooxygenase (COX), known to be activated or overexpressed, respectively, in pancreatic cancer. We have previously shown that parthenolide, a proapoptotic drug associated with NF-KB inhibition, enhanced the growth suppression of pancreatic cancer cells by the COX inhibitor sulindac in vitro. In the present study, a bioavailable analogue of parthenolide, LC-1, and sulindac were evaluated in vivo using a xenograft model of human pancreatic cancer. Treatment groups included placebo, low-dose/high-dose LC-1 (20 and 40 mg/kg), low-dose/ high-dose sulindac (20 and 60 mg/kg), and low-dose combination LC-1/sulindac (20 mg/kg each). In MiaPaCa-2 xenografts, tumor growth was inhibited by either highdose sulindac or LC-1. In BxPC-3 xenografts, tumor size was significantly reduced by treatment with the low-dose LC-1/sulindac combination or high-dose sulindac alone (P < 0.05). Immunohistochemistry of BxPC-3 tumors revealed a significant decrease in Ki-67 and CD31 staining by high-dose sulindac, with no significant changes in COX-1/ COX-2 levels or activity in any of the treatment groups. NF-KB DNA-binding activity was significantly decreased by high-dose LC-1. Cyclin D1 protein levels were reduced by the low-dose LC-1/sulindac combination or high-dose sulindac alone, correlating with BxPC-3 tumor suppression. These results suggest that LC-1 and sulindac may mediate their antitumor effects, in part, by altering cyclin D1 levels. Furthermore, this study provides preclinical evidence for the therapeutic efficacy of these agents. [Mol Cancer Ther 2007;6(6):1736 -44]

Efficacy of Dimethylaminoparthenolide and Sulindac in Combination With Gemcitabine in a Genetically Engineered Mouse Model of Pancreatic Cancer

“…30 Subsequently, we also demonstrated that combination chemotherapy with sulindac and DMAPT in vivo suppresses tumor growth in association with cyclin D1 inhibition in BxPC-3 xenograft tumors. 21 In a hamster carcinogen-induced developmental model of pancreatic cancer, DMAPT alone significantly decreases the size of gross pancreatic cancers relative to placebo; the combination of DMAPT/ celecoxib prevents both tumor invasion and metastasis. 20 Despite demonstrating potential chemotherapeutic efficacy, DMAPT and celecoxib, alone or in combination, do not exhibit chemopreventive activity in this carcinogen-induced model.…”

“…The dose of DMAPT chosen for this study was the same as that previously shown to inhibit NF-JB in both xenograft and carcinogeninduced animal models. 20,21 Dimethylaminoparthenolide is currently being evaluated in clinical trials; however, doses of 50 to 100 mg/kg have been used in vivo in canine and mouse models to inhibit NF-JB, without any evidence of toxicity. 34 In the genetically engineered mouse model, we also show that combination DMAPT treatment decreases NF-JB expression in the pancreatic lesions.…”

“…19 In xenograft and carcinogen-induced animal models of pancreatic cancer, we demonstrated that DMAPT inhibits the activity of NF-JB and shows therapeutic promise in combination with the anti-inflammatory agents sulindac (nonselective COX inhibitor) or celecoxib (specific COX-2 inhibitor) in vivo. 20,21 We and others have also reported that the chemotherapeutic agent gemcitabine induces NF-JB activity in pancreatic cancer cells in vitro, suggesting that NF-JB may play a role in chemoresistance to gemcitabine. 9,22Y25 We recently demonstrated that DMAPT not only suppresses gemcitabine-induced NF-JB activation but also sensitizes pancreatic cancer cells to the antiproliferative effects of gemcitabine in vitro, indicating that the level of NF-JB activity modulates the gemcitabine response (in press).…”

Radio-sensitization of the murine osteosarcoma cell line LM8 with parthenolide, a natural inhibitor of NF-κB

“…Despite widely documented anti-cancer activity and the absence of major adverse effects, clinical development of parthenolide is hampered by its poor water solubility, (35) thus limiting its potential as a promising clinical agent. Previous studies investigated the in vitro and in vivo activities of the water-soluble parthenolide analogue dimethylaminoparthenolide (DMAPT) (20,35,36) and reported that this analogue suppressed tumor growth by targeting NF-κB and generating reactive oxygen (37)(38)(39). The water-soluble parthenolide analogue may become a more readily available radio-sensitizing agent, but further investigation is needed to elucidate its efficacy and spectrum as a radio-sensitizing agent.…”

Nuclear Factor-κB Inhibition by Parthenolide Potentiates the Efficacy of Taxol in Non–Small Cell Lung Cancer In vitro and In vivo

“…Several studies have proposed that parthenolide inhibits NF-κB DNA binding activity and function and thereby increases the sensitivity of breast cancer cells to the chemotherapeutic agent Taxol (24). Although the effect of parthenolide as an inhibitor of NF-κB activity has been reported previously in several cancer cell lines (22,23,25,26), its significance, detailed mechanism, potential use in treatment, and adjuvant approach in combination with Taxol chemotherapy has not yet fully been investigated in human non-small cell lung cancer (NSCLC).…”