In Vitro and In Vivo Antitumor Activity of Cucurbitacin C, a Novel Natural Product From Cucumber.

Dinglan Wu,Muqi Lin,Xiaomin Luo,Yi Shang,Weiren Huang,Fei Wang,Zhu Wang,Xiantong Zhang,Jiayi Zhou

doi:10.3389/fphar.2019.01287

Abstract

Cucurbitacin C (CuC), a novel analogue of triterpenoids cucurbitacins, confers a bitter taste in cucumber. Genes and signaling pathways responsive for biosynthesis of CuC have been identified in the recent years. In the present study, we explored the anti-cancer effects of CuC against human cancers in vitro and in vivo. CuC inhibited proliferation and clonogenic potential of multiple cancer cells in a dose-dependent manner. Low-dose CuC treatment induced cell cycle arrest at G1 or G2/M stage in different cancer lines, whereas high-dose treatment of CuC caused apoptosis in cancer cells. PI3K-Akt signaling pathway was found to be one of the major pathways involved in CuC-induced cell growth arrest and apoptosis by RNA-Seq and Western blotting. Mechanistic dissection further confirmed that CuC effectively inhibited the Akt signaling by inhibition of Akt phosphorylation at Ser473. In vivo CuC treatment (0.1 mg/kg body weight) effectively inhibited growth of cancer cell-derived xenograft tumors in athymic nude mice and caused significant apoptosis. Our findings for the first time demonstrated the potential therapeutic significance of CuC against human cancers.

Highlights

Cucurbitacins are triterpenoid molecules originally isolated as bitter principles from Cucurbitaceae plants
We showed for the first time that the natural product Cucurbitacin C (CuC) inhibited cancer cell growth in vitro and in vivo by induction of growth arrest, cellular migration inhibition, and apoptosis in several types of cancer cells
A 0–200-nM serial dilution of CuC was used to determine the optimal concentrations for CuC inhibition, and the results showed that 40%–60% inhibition rates distributed in the range of 10–100 nM CuC concentrations and PC-3 and T24 exhibited the highest inhibition rates among these cancer lines, which were consistent with their the half maximal inhibitory concentration (IC50) patterns (Figure 2C)

Summary

Introduction

Cucurbitacins are triterpenoid molecules originally isolated as bitter principles from Cucurbitaceae plants. The anti-cancer activities of cucurbitacins through antiproliferation (Mao et al, 2019; Saeed et al, 2019), inhibition of migration and invasion (Touihri-Barakati et al, 2017; Zou et al, 2018), induction of cell apoptosis (Ding et al, 2017; He et al, 2017; Liu et al, 2018; Mao et al, 2019), autophagy (Ni et al, 2018; Lin et al, 2019), and cell cycle arrest promotion are of great interest (Liu et al, 2018). Cucurbitacins B, D, E, and I are the most wildly studied variants and exhibit general in vitro and in vivo anti-cancer effects.

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