Parthenolide Sensitizes Human Colorectal Cancer Cells to Tumor Necrosis Factor-related Apoptosis-inducing Ligand through Mitochondrial and Caspase Dependent Pathway

Abstract

Background/AimsCombination therapy utilizing tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) in conjunction with other anticancer agents, is a promising strategy to overcome TRAIL resistance in malignant cells. Recently, parthenolide (PT) has proved to be a promising anticancer agent, and several studies have explored its use in combination therapy. Here, we investigated the molecular mechanisms by which PT sensitizes colorectal cancer (CRC) cells to TRAIL-induced apoptosis.MethodsHT-29 cells (TRAIL-resistant) were treated with PT and/or TRAIL for 24 hours. The inhibitory effect on proliferation was detected using the 3-(4, 5-dimethylthiazol-2yl)-2, 5-diphenyltetrazolium bromide (MTT) assay. Annexin V staining, cell cycle analysis, and Hoechst 33258 staining were used to assess apoptotic cell death. Activation of an apoptotic pathway was confirmed by Western blot.ResultsTreatment with TRAIL alone inhibited the proliferation of HCT 116 cells in a dose-dependent manner, whereas proliferation was not affected in HT-29 cells. Combination PT and TRAIL treatment significantly inhibited cell growth and induced apoptosis of HT-29 cells. We observed that the synergistic effect was associated with misregulation of B-cell lymphoma 2 (Bcl-2) family members, release of cytochrome C to the cytosol, activation of caspases, and increased levels of p53.ConclusionCombination therapy using PT and TRAIL might offer an effetive strategy to overcome TRAIL resistance in certain CRC cells.

Goniothalamin enhances TRAIL-induced apoptosis in colorectal cancer cells through DR5 upregulation and cFLIP downregulation

“…TRAIL triggered death receptor mediated apoptosis pathway via binding to death receptor DR5 resulting in induction cleavage of Bid to tBid, then crosslinking to of subG1 phase population in cell cycle, increased cell surface phosphatidyl-serine presentation and increased phosphorylation of H2AΧ were observed under the combined treatment of TRAIL and goniothalamin, indicating apoptosis induction in LoVo cells as compared to a single treatment with TRAIL or goniothalmin alone (62)(63)(64)(65). Similar reports of other compounds sensitize TRAIL-induced apoptosis include inostamycin (19), delphinidin (66), and parthenolide (67). Therefore, the combined treatment of TRAIL and goniothalamin enhanced cytotoxicity in TRAIL refractory LoVo cells through caspase-dependent apoptosis pathway in both death receptor-and mitochondrial-mediated pathways.…”

Combined Parthenolide and Balsalazide Have Enhanced Antitumor Efficacy Through Blockade of NF-κB Activation

“…In our previous studies, we found that parthenolide can be a potential chemopreventive and therapeutic agent for colorectal cancer and CAC (17,18). We have also shown that parthenolide has potential to be applied in combination therapy for colorectal cancer treatment: combination with 5-fluorouracil (5-FU) can overcome 5-FU resistance in human colorectal cancer, and parthenolide sensitizes cancer cells to the TNF-related apoptosisinducing ligand (TRAIL) in TRAIL-resistant colorectal cancer cells (29)(30)(31). These findings indicate that parthenolide may increase the efficacy of balsalazide in preventing carcinogenesis caused by chronic inflammation.…”

Down‐regulation of intracellular anti‐apoptotic proteins, particularly c‐FLIP by therapeutic agents; the novel view to overcome resistance to TRAIL

“…Additionally, some of the agents that their combined using with TRAIL has been acceptable outcomes but in limited cell lines have been listed below. kurarinone (Seo et al, ; Zhou, Cao, Wang, & Wu, ), monensin (Yoon et al, ), paxiline (Kang et al, ), diclofenac/hyaluronic acid (Dic/HA) (Fecker et al, ), nickel2+ (Schmidt et al, ), SHetA2 (Lin et al, ), BAY 11–7085 (Shen et al, ), compound c (Jang et al, ), FAK inhibitor PH11 (Dao et al, ), caffeic acid phenethyl ester (CAPE) (Li, Wu, et al, ), fasudil (Wang et al, ), cathepsin S inhibitor ZFL (Seo et al, ), 4‐(4‐Chloro‐2‐methylphenoxy)‐N‐hydroxybutanamide (CMH) (Bijangi‐Vishehsaraei, Huang, Safa, Saadatzadeh, & Murphy, ), actinomycin (Haimerl, Erhardt, Sass, & Tiegs, ), H1 (derivative of tetrandrine) (Lin, Wang, et al, ), genistein (Siegelin, Siegelin, Habel, & Gaiser, ), icaritin (Han, Xu, et al, ), ABT‐737 and VX–680 (Choi et al, ), 6‐shogaol (Han, Woo, et al, ), cathepsin E (Yasukochi, Kawakubo, Nakamura, & Yamamoto, ), ozarelix (Festuccia et al, ), transglutaminase 2 inhibitor (TGM2I) (Li, Xu, Bai, Chen, & Lin, ), amurensin G (Kim, Kim, Lee, et al, ), volasertib (Jeon et al, ), temozolomide (TMZ) (Zhitao, Long, Jia, Yunchao, & Anhua, ), chalcone‐24 (Xu et al, ), gingerol (Lee, Kim, Jung, Lee, & Park, ), triptolide (Chen et al, ), AKT inhibitor API‐1 (Li, Ren, et al, ), smac mimetic compounds (SMC) (Cheung et al, ), dicoumarol (Park, Min, Choi, & Kwon, ), partenolide (Trang et al, ), Pyrrolo‐1, 5‐benzoxazepine (PBOX) (Nathwani et al, ), embelin (Siegelin, Gaiser, & Siegelin, ), myricetin (Siegelin, Gaiser, Habel, & Siegelin, ), quercetin (Jung, Heo, Lee, Kwon, & Kim, ), silibinin (Son et al, ), epigallocatechin gallate (EGCG) (Abou El Naga et al, ), icariside II (Du et al, ), anisomycin (Seo et al, ), dioscin (Kim, Kim, Park, et al, ), celecoxib (Chen et al, ), micro RNA 126 (MiR‐126) (Zhang, Zhou, Zhu, & Yuan, ), gambognic acid (Ye et al, ), survivin inhibitor YM155 (Woo, Min, Seo, &...…”