Deoxyelephantopin induces apoptosis via oxidative stress and enhances gemcitabine sensitivity in vitro and in vivo through targeting the NF-κB signaling pathway in pancreatic cancer

Abstract

Pancreatic cancer is a highly invasive malignant tumor of the digestive system with an unfavorable prognosis worldwide. This trait is thought to be largely attributed to chemoresistance. Chemotherapy is the only hope for patients with advanced pancreatic cancer. Therefore, seeking new effective chemotherapy drugs has become an urgent need. The purpose of our study was to explore whether deoxyelephantopin (DET), a sesquiterpene lactone, has a potential antitumor effect in pancreatic cancer. Additionally, the antitumor effects of DET alone or in combination with gemcitabine (GEM) and the potential mechanism of this combination were revealed. In vitro experiments showed that DET suppressed the proliferation, invasion and metastasis of pancreatic cancer cells, induced cell apoptosis via oxidative stress, and enhanced GEM sensitivity by inhibiting the NF-κB signaling pathway. Beyond that, in vivo experiments showed that DET not only inhibited pancreatic tumor growth and metastasis but also amplified the antitumor capacity of GEM, which was related to the downregulation of NF-κB and its downstream gene products. In summary, it is possible that DET could be developed as a single agent or combined with conventional chemotherapy drugs to improve the treatment of pancreatic cancer.

Sesquiterpene Lactones as Promising Candidates for Cancer Therapy: Focus on Pancreatic Cancer

“…The potential antitumor effect in pancreatic cancer of deoxyelephantopin (DET) ( 7 ), a natural sesquiterpene lactone isolated from the Chinese herbal medicine Elephantopus scaber (Asteraceae), was evaluated by Ji et al [ 98 ]. The antitumor effects of DET were evaluated alone and in combination with gemcitabine.…”

Deoxyelephantopin and Its Isomer Isodeoxyelephantopin: Anti-Cancer Natural Products with Multiple Modes of Action

“…DET has been demonstrated to induce intrinsic apoptosis in many types of cancer cell lines, including human osteosarcoma, pancreatic cancer, cervical cancer, breast cancer, lung cancer, nasopharyngeal cancer, colorectal cancer, and liver cancer cell lines through Bcl-2 family protein modulation. DET dose-dependently induces apoptosis through increased levels of pro-apoptosis Bax and decreased levels of anti-apoptosis Bcl-2, with the resultant activation of caspase-9, caspase-3, cytochrome c release, and PARP cleavage in human osteosarcoma cell lines, MG-63 and U2OS (4, 8, 16, and 32 µM) [ 71 ], and human pancreatic cancer cell lines, BxPC-3 (30 and 50 µM) and CFPAC-1 (40 and 60 µM) [ 72 ]. Similarly, Chim-Kei Chan et al has reported that DET (0.75, 1.5, and 3.0 µg/mL) induced a concentration-dependent upregulation of cleaved caspase-3 and cleaved PARP protein expression in HCT116 cells [ 34 ].…”

“…In BxPC-3 and CFPAC-1 cells, ROS generation was induced as early as 0.5 h, and reached its maximum level at 2 and 3 h of DET incubation (50 and 60 µM, respectively). DET dissipated ΔΨm, modulated the GSH/GSSG ratio, and depleted Trx activity in BxPC-3 cells (DET at 30 and 50 µM) and CFPAC-1 cells (DET at 40 and 60 µM) [ 72 ]. DET (2 mg/mL) induced c-Jun N-terminal kinase (JNK) activation through ROS generation, causing cell death in TS/A cells.…”

“…DET inhibited the translocation of NF-κB-p65 in the same way as IKK-16. DET (30 μM) inhibited TNF-α- (50 ng) and gemcitabine-induced (50 μM) NF-κB activation with a concomitant regulation of related downstream gene products of NF-κB, including Ki-67, PCNA, and E-cadherin [ 72 ]. DET (12.28 µg/mL) has been shown to induce the inhibition of NF-κB activation at the transcriptional level by reducing the gene expression of NF-κB and IκB in A549 cells.…”

Sesquiterpene Lactones Potentiate Olaparib-Induced DNA Damage in p53 Wildtype Cancer Cells

“…We next set out to test if BdS could extend olaparib usage by other mechanisms. For example, ATL, a sesquiterpene lactone reminiscent in structure to IJ-5 and BdS (Figure 1C), can increase ROS levels in a number of transformed cell lines, which could explain the increased BdS sensitivity of Kuramochi cells given their pre-existing replication stress vulnerability (Figure 2C) [14,[38][39][40][41]. Importantly, the increased ROS levels induced by ATL can lead to oxidative DNA damage, marked particularly by the formation of the DNA base oxidation product 8-oxo-7,8-dihydroguanine (8-OxoG), which triggers the induction of base excision repair (BER) [14].…”