Bigelovin triggered apoptosis in colorectal cancer in vitro and in vivo via upregulating death receptor 5 and reactive oxidative species

Abstract

Colorectal cancer (CRC) is the third most prevalent cancer and the third highest cancer-related mortality in the United States. Bigelovin, a sesquiterpene lactone isolated from Inula helianthus aquatica, has been proven to induce apoptosis and exhibit anti-inflammatory and anti-angiogenic activities. However, the effects of bigelovin on CRC and underlying mechanisms have not been explored. The present study demonstrated that bigelovin exhibited potent anti-tumor activities against CRC in vitro and in vivo. Bigelovin suppressed cell proliferation and colony formation and induced apoptosis in human colorectal cancer HT-29 and HCT 116 cells in vitro. Results also revealed that bigelovin activated caspases, caused the G2/M cell cycle arrest and induced DNA damage through up-regulation of death receptor (DR) 5 and increase of ROS. In HCT 116 xenograft model, bigelovin treatment resulted in suppression of tumor growth. Bigelovin at 20 mg/kg showed more significant tumor suppression and less side effects than conventional FOLFOX (containing folinic acid, 5-fluorouracil and oxaliplatin) treatment. In addition, in vivo data confirmed that anti-tumor activity of bigelovin in CRC was through induction of apoptosis by up-regulating DR5 and increasing ROS. In conclusion, these results strongly suggested that bigelovin has potential to be developed as therapeutic agent for CRC patients.Colorectal cancer is one of the top three most common cancer and the third leading cause of cancer-related death in the United States 1 . In 2016, American Cancer Society (ACS) estimates that 134,490 persons will be diagnosed having colorectal cancer (CRC), and more than one-third will die from this cancer 2 . Although the incidence and mortality rate of CRC in developed countries declined during the last decade mainly due to the early screen in asymptomatic and average risk people 2,3 , incidence and mortality rate are still growing in developing world with increasing westernized lifestyle and aging population 3 . Surgery is the primary treatment for most of the CRC patients 4 . For patients in higher level of metastatic stage, radiation and chemotherapy often accompany with surgery. Currently, fluorouracil (5-Fu) is often used alone or combined with folinic acid and oxaliplatin as FOLFOX to treat primary colon cancer. For advanced or metastatic CRC, FOLFOX and FOLFIRI (5-Fu, folinic acid and irinotecan) are the most commonly used chemotherapy combinations. Despite the effectiveness of the chemotherapy and radioactive therapy, the high incidence (up to 98%) of side effects, including hair loss, nausea, vomiting, neurotoxicity, increasing the chance of infection and immune system suppression often affect the quality of life 5,6 . Targeted therapy to vascular endothelial growth factor (e.g. bevacizumab) or epidermal growth factor receptor (e.g. cetuximab) are common adjuvant/alternative treatments for CRC 7 . Although they are reported to

Sesquiterpenes α-humulene and β-caryophyllene oxide enhance the efficacy of 5-fluorouracil and oxaliplatin in colon cancer cells

“…One could be based on sesquiterpene ability to increase oxidative stress in cancer cells (2). For example, bigelovin, a sesquiterpene lactone isolated from Inula helianthus aquatica, has been (9). Treatment of bladder cancer T24 cells with costunolide resulted in a dose-dependent inhibition of cell viability and induction of apoptosis, which was associated with ROS generation (10).…”

Oxidative Stress Modulation and ROS‐Mediated Toxicity in Cancer: A Review on In Vitro Models for Plant‐Derived Compounds

“…Consequently, in vivo experiments with animal models might be optimized based on in vitro data. Information from in vitro and in vivo studies will, in turn, facilitate and improve further clinical trials [ 49 ].…”

“…The effect of this sesquiterpene lactone naturally produced by Inula helianthus aquatic on HT-29 and HCT 116 colorectal cancer cell lines was studied in a recent work by Li et al [ 49 ]. The authors found a marked antiproliferative effect caused by apoptosis induction.…”

In vitro and in vivo anti-cancer activity of silymarin on oral cancer

“…Previously, several studies reported that natural compounds such as ginsenoside compound K and bigelovin induced DR5 to activate the extrinsic apoptosis pathway in colon cancer cell lines. 22,23 Our research group also reported that the methanol extract of Smilax china L. or b-phenylethyl isothiocyanate induced the DR5/caspase-8/Bid axis by regulating the extracellular signal-regulated kinase (ERK) or p38 MAPK signaling pathway, leading to caspase-mediated apoptosis in oral or cervical cancer cells. [24][25][26][27] These previous findings fully support DR5 regulation by natural products during apoptotic cell death pathways in cancer.…”