Pharmacologic downregulation of c‐FLIP_L restores juxtacrine death receptor‐mediated apoptosis in cancer cells in a peritoneal carcinomatosis model

Abstract

Metastasis occurs when circulating cancer cells implant in normal secondary tissues. Paradoxically, many cancer cells express death receptors while many normal tissues express the cognate death receptor ligands, suggesting that cancer cells possess mechanisms to inhibit death receptor signaling. Pharmacological restoration of juxtacrine‐mediated death receptor signaling could prevent cancer cells from implanting in normal tissues such as the peritoneum. The results showed that BAY 11‐7085 significantly inhibited peritoneal carcinomatosis in mice following the introduction of colon and pancreatic cancer cell lines into the intra‐abdominal cavity. Treatment with BAY 11‐7085 restored juxtacrine death receptor signaling during the adhesion of the cancer cells to mesothelial cells, which line the peritoneum. BAY 11‐7085 rapidly inhibited c‐FLIPL expression in colon and pancreatic cancer cell lines during adhesion to mesothelial cells. Pancreatic cancer cells sorted for high c‐FLIPL expression formed peritoneal implants much more readily than cells with low c‐FLIPL expression, and RNAi inhibition of c‐FLIPL in colon cancer cells dramatically reduced peritoneal implantation. This is a novel demonstration that the restoration of death receptor‐mediated apoptotic signaling in cancer cells through the pharmacological inhibition of c‐FLIPL can inhibit tumor implantation in a clinically relevant model of peritoneal carcinomatosis, a fatal disease. Pharmacological inhibitors of FLIP hold promise as a way to curtail cancer cell colonization of secondary tissues.

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, &...…”

Design, Synthesis, and Biological Evaluation of Sulfonyl Acrylonitriles as Novel Inhibitors of Cancer Metastasis and Spread

“…21 We showed that when cancer cells adhere to mesothelial cells, the death receptor ligands expressed by mesothelial cells can activate death receptors expressed on cancer cells in a juxtacrine fashion, which results in apoptosis if 1 is present. 19 Thus, 1-mediated inhibition of c-FLIP expression restores death receptor-mediated cancer cell apoptosis during their adhesion to normal human mesothelial cells. 19 In a recent study, several analogues of 1 were synthesized to determine the role of the sulfonylacrylonitrile moiety and assess the potential of an amide replacement for the tert-butyl fragment of 1.…”

“…19 Thus, 1-mediated inhibition of c-FLIP expression restores death receptor-mediated cancer cell apoptosis during their adhesion to normal human mesothelial cells. 19 In a recent study, several analogues of 1 were synthesized to determine the role of the sulfonylacrylonitrile moiety and assess the potential of an amide replacement for the tert-butyl fragment of 1. 22 While studies of these analogues pointed out the importance of the functional groups to the pro-apoptotic efficacy of 1, few of the analogues demonstrated increased efficacy in pancreatic, ovarian, or colon cancer cells compared with the parent compound.…”

“…19 Many cancer cells express death receptors of the TNFα superfamily yet evade death receptor-mediated apoptosis through the overexpression of survival proteins such as c-FLIP. 19 The overexpression of death receptors by cancer cells appears to be conserved, as they have been shown to mediate cancer cell proliferation. 20 Many normal tissues contain cells, such as mesothelial cells, that express cognate death receptor ligands.…”

“…As we previously showed, compound 1 rapidly and strongly induces apoptosis of cancer cells during adhesion. 19 The most active analogues in the coculture assay were tested for their ability to induce apoptosis of A2780 ovarian cancer cells by demonstrating increased cellular levels of cleaved PARP and cleaved caspase 3, which are indicators of apoptosis. While all of the analogues induced apoptosis to a degree, analogues 6b and 13a showed similar levels of apoptotic induction as compound 1 (Figure 2).…”