Enhanced anti-tumor effect of combination therapy with gemcitabine and apigenin in pancreatic cancer

Abstract

Apigenin is a dietary flavonoid possessing therapeutic potential against cancers. This study was designed to investigate whether combination therapy with gemcitabine and apigenin enhanced anti-tumor efficacy in pancreatic cancer. In vitro, the combination treatment resulted in more growth inhibition and apoptosis through the down-regulation of NF-κB activity with suppression of Akt activation in pancreatic cancer cell lines (MiaPaca-2, AsPC-1). In vivo, the combination therapy augmented tumor growth inhibition through the down-regulation of NF-κB activity with the suppression of Akt in tumor tissue. The combination of gemcitabine and apigenin enhanced anti-tumor efficacy through Akt and NF-κB activity suppression and apoptosis induction.

Introduction

Because of difficulties in early diagnosis and highly aggressive malignant behavior, only 10–20% of pancreatic cancers can be surgically resected with curative intent at the time of diagnosis and most patients experience local recurrence and metastasis [1]. Although gemcitabine can prolong survival of patients and is the current standard therapy for advanced pancreatic cancer, only less than 5% survive 5 years after the initial diagnosis and the median survival duration is not over than 6 months [2], [3], [4] due to a high degree of inherent and acquired chemoresistance. The low cure rate in pancreatic carcinoma is partly because of the lack of an effective chemotherapeutic regimen to overcome chemoresistance. To obtain an effective regimen, a careful and well-designed combination of multi-therapeutic agents with different modes of action will be required. However, multi-agent chemotherapy contributes to added toxicity and has no significant survival benefit in spite of high response rate.

In recent years, novel strategies for sensitizing pancreatic tumor cells with naturally occurring dietary chemopreventive compounds have gained considerable attention because of their beneficial effects in overcoming tumor cell resistance to apoptosis [5]. A nontoxic nutritional agent like soy isoflavone such as genistein, which already has shown ability to inhibit nuclear factor-κB (NF-κB) effectively in pancreatic carcinoma may represent an attractive approach to improve the treatment of pancreatic tumors [6], [7]. Apigenin (4′,5,7,-trihydroxyflavone) is a common dietary flavonoid. Apigenin is a chemopreventive compound [8], [9] as an inhibitor of certain signal transduction pathways [10] and has recently been shown to possess anti-tumor properties by induction of growth inhibition, cell cycle arrest, and apoptosis in many human carcinoma cells [11], [12], [13], [14], [15]. Furthermore, it has low toxicity, is not mutagenic and is widely distributed in many fruits and vegetables including parsley, onions, oranges, tea, chamomile, wheat sprouts, and in some seasonings [12]. Apigenin has also been shown to down regulate NF-κB through the inhibition of Akt [16], [17].

Based on previous results, we hypothesized that apigenin may induce the inhibition of Akt and down regulation of NF-κB signaling pathways that are known to confer a high degree of chemoresistance by pancreatic cancer cells, thereby abrogating either de novo or acquired chemoresistance. We report our preclinical observations in support of our hypothesis that better cell killing is feasible by presensitizing pancreatic cancer cells with apigenin during gemcitabine-induced killing through the inhibition of Akt and down regulation of NF-κB in vitro and in vivo using our pancreatic cancer xenograft model.