Abstract
Cucurbitacin B (CuB) is a natural tetracyclic triterpene product and displays antitumor activity across a wide array of cancers. In this study, we explored the anti-pancreatic cancer activity of CuB alone and in combination with SCH772984, an ERK inhibitor, in vitro and in vivo. CuB inhibited proliferation of pancreatic cancer cells by arresting them in the G2/M cell cycle phase. This was associated with inhibition of EGFR expression and activity and downstream signaling, including PI3K/Akt/mTOR and STAT3. Interestingly, ERK activity was markedly enhanced by activating AMPK signaling after 12 h of CuB treatment. SCH772984 potentiates the cytotoxic effect of CuB on pancreatic cancer cells through complementary inhibition of EGFR, PI3K/Akt/mTOR, STAT3 and ERK signaling, followed by an increase in the pro-apoptotic protein Bim and a decrease in the anti-apoptotic proteins Mcl-1, Bcl-2, Bcl-xl and survivin. Furthermore, combined therapy with CuB and SCH772984 resulted in highly significant growth inhibition of pancreatic cancer xenografts. These results may provide a basis for further development of combining CuB and ERK inhibitors to treat pancreatic cancer.
Highlights
Pancreatic cancer is the fourth most common cause of cancer deaths in Western societies, and fewer than 5% of newly diagnosed patients survive more than 5 years [1]
This indicates that Cucurbitacin B (CuB) has stronger growth inhibitory effects on pancreatic cancer cells compared to normal pancreatic ductal epithelial cells after 72 h of treatment
We examined the association between the growth inhibitory effect of CuB and Epidermal growth factor receptor (EGFR) signaling in BxPC3 and HPAC cells
Summary
Pancreatic cancer is the fourth most common cause of cancer deaths in Western societies, and fewer than 5% of newly diagnosed patients survive more than 5 years [1]. The low survival rate is primarily due to the insensitivity of pancreatic cancer to most chemotherapy and radiotherapy treatments [1, 2]. There is an urgent need to develop new agents or combination therapeutic strategies to treat this deadly disease. Epidermal growth factor receptor (EGFR) plays an important role in pancreatic cancer progression [3]. EGFR is a member of the erb-B receptor tyrosine kinase (TK) family. The activated receptor can induce several downstream signaling pathways, including Ras/Raf/ mitogen-activated extracellular signal-regulated kinase/
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