Abstract 4109: Cucurbitacin B: A novel natural agent for the management of non-small cell lung cancer

Abstract

Lung cancer is the primary cause of cancer death in both men and women in the United States and worldwide. The general prognosis is still very low despite of developments in the treatment due to improved surgical techniques, increased application of combined modality treatments and the use of new drugs. Since the past decade, researchers have been investigating a range of purified compounds from dietary sources as possible anticancer drugs. The main issue with the use of natural products is their effectiveness at high doses which generally could not be delivered to humans through dietary consumption. Here, we observed that cucurbitacin B exhibits antiproliferative effects on human non-small cell lung cancer (NSCLC) cells at very low concentrations. The cucurbitacins are highly diverse and oxygenated tetracyclic triterpenoids isolated from plants of Cucurbitaceae family which are well-known for their bitterness of edible products like pumpkins, gourds and squashes. Cucurbitacin B is one of the most abundant and has been most widely used. In this study, we determined the effect of cucurbitacin B on the inhibition of cell-growth and suppression of phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling in human NSCLC cells. Treatment of cucurbitacin B (0.2-0.6 μM; 24 h) was found to result in 34-61% and 45-65% decrease in the viability of human NSCLC H1792 and A549 cells respectively, but had only minimal effect on normal human bronchial epithelial cells. The IC50 of cucurbitacin B in these cells ranged from 0.43-0.49 μM. The A549 cell colonies were also reduced by treatment with cucurbitacin B in a dose-dependent manner. It has been well documented that mTOR functions downstream of the PI3K/Akt pathway and is phosphorylated in response to stimuli that activate the PI3K/Akt pathway. Treatment of A549 cells with cucurbitacin B (0.2-0.6 μM; 24 h) caused decrease in the protein expression of PI3K (p85 and p110) and inhibition of the phosphorylation of Akt and mTOR. PI3K/Akt-dependent phosphorylation signals through tuberin, the protein product of tuberous sclerosis complex (TSC)1/TSC2 complex, which leads to activation of mTOR. The mTOR also phosphorylates eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) which disassociates from the eukaryotic translation initiation factor (eIF) 4E, allowing activation of protein translation. Treatment of A549 cells with cucurbitacin B also caused inhibition of the phosphorylation of p70S6K1, eIF-4E and 4E-BP1 and downstream targets of mTOR. In cucurbitacin B treated cells, there was also inhibition of the constituents of mTOR signaling complex such as Rictor, Raptor, GβL and PRAS40 and activation of AMP-activated protein kinase (AMPKα) and tuberous sclerosis complex (TSC)2. We suggest that cucurbitacin B could be developed as an agent for the management of lung cancer. Citation Format: Naghma Khan, Farah Jajeh, Sameh M. Shabana, Hasan Mukhtar. Cucurbitacin B: A novel natural agent for the management of non-small cell lung cancer. [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 4109. doi:10.1158/1538-7445.AM2014-4109