Last update 01 Nov 2024

XIAP x TRAIL

Last update 01 Nov 2024

Basic Info

Related Targets

XIAPTRAIL

Drugs associated with XIAP x TRAIL

AD-O53.2

Target

TRAIL x XIAP

Mechanism

TRAIL modulators [+1]

Active Org.-

Originator Org.

Adamed Consumer Healthcare SA

Active Indication-

Inactive Indication

Neoplasms

Drug Highest PhasePending

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with XIAP x TRAIL

100 Translational Medicine associated with XIAP x TRAIL

0 Patents (Medical) associated with XIAP x TRAIL

378

Literatures (Medical) associated with XIAP x TRAIL

01 Apr 2024·Asia-Pacific Journal of Clinical Oncology

Construction and validation of a novel tumor necrosis factor‐related apoptosis‐inducing ligand mutant MuR5S4‐TR

Article

Author: Liu, Xia ; Sun, Lei ; Zhao, Yaqin ; Yi, Cheng ; Zhu, Hong ; He, Jianping

AbstractAimTumor necrosis factor‐related apoptosis‐inducing ligand (TRAIL) can selectively kill tumor cells but has no significant effect on normal cells. However, the use of TRAIL is limited for resistance by more than 50% of the tumor cell lines. It's very important to develop a more efficient form of TRAIL for cancer treatment.MethodsThe N‐terminal in soluble fragments (114–281aa) of TRAIL was redesigned to construct a novel TRAIL mutant‐MuR5S4‐TR. The Cell Counting Kit‐8 method to explore the antitumor effects. The potential mechanisms were also explored.ResultsNovel TRAIL mutant with cell‐penetrating peptides (CPP) like and Second mitochondria‐derived activator of caspases (Smac) like structure‐MuR5S4‐TR was successfully constructed. The prokaryotic expression system was successfully built, and the MuR5S4‐TR was purified and reconfirmed by western blot. MuR5S4‐TR could enhance the antitumor effects of TRAIL in most of the cancer cell lines significantly, NCI‐H460 lung cancer cell line, for instance. After MuR5S4‐TR treatment, the expressions of death receptor 4 (DR4), DR5, Caspase‐8, and cleaved Caspase‐3 were remarkably increased, however, there was no significant difference in X‐linked inhibitor of apoptosis expression.ConclusionWe constructed a novel TRAIL mutant with CPP‐like and Smac‐like structure‐MuR5S4‐TR. The MuR5S4‐TR showed significantly stronger antitumor effects than TRAIL in many tumor cell lines. The MuR5S4‐TR showed strong antitumor effects both in vitro and in vivo. This preliminary study implies that MuR5S4‐TR may be a more efficient form of TRAIL for cancer therapy.

07 Jun 2023·Medical oncology (Northwood, London, England)

Evaluation of the anticancer effect of telomerase inhibitor BIBR1532 in anaplastic thyroid cancer in terms of apoptosis, migration and cell cycle.

Article

Author: Turkmen, Ecem ; Biray Avci, Cigir ; Sogutlu, Fatma ; Erdogan, Mehmet

Anaplastic thyroid cancer (ATC) represents the type with the worst prognosis among thyroid cancers. In ATC with a highly invasive phenotype, selective targeting of TERT with BIBR1532 may be a goal-driven approach to preserving healthy tissues. In present study, it was aimed to investigate the effects of treatment of SW1736 cells with BIBR1532 on apoptosis, cell cycle progression, and migration. The apoptotic effect of BIBR1532 on SW1736 cells was examined using the Annexin V method, the cytostatic effect using cell cycle test, migration properties using wound healing assay. Gene expression differences were determined by real-time qRT-PCR and differences in protein level by ELISA test. BIBR1532-treated SW1736 cells had 3.1-fold increase in apoptosis compared to their untreated counterpart. There was 58.1% arrest in the G₀/G₁ phase and 27.6% arrest in the S phase of the cell cycle in untreated group, treatment with BIBR1532 increased cell population in G₀/G₁ phase to 80.9% and decreased in S phase to 7.1%. Treatment with the TERT inhibitor resulted in a 50.8% decrease in cell migration compared to the untreated group. After BIBR1532 treatment of SW1736 cells, upregulation of BAD, BAX, CASP8, CYCS, TNFSF10, CDKN2A genes, and downregulation of BCL2L11, XIAP, CCND2 genes were detected. BIBR1532 treatment resulted in an increase in BAX and p16 proteins, and a decrease in concentration of BCL-2 protein compared to untreated group. Targeting TERT with BIBR1532 as a mono drug or using of BIBR1532 at "priming stage" prior to chemotherapy treatment in ATC may present a novel and promising treatment strategy.

01 Jan 2023·American journal of cancer research

ONC201/TIC10 plus TLY012 anti-cancer effects via apoptosis inhibitor downregulation, stimulation of integrated stress response and death receptor DR5 in gastric adenocarcinoma.

Article

Author: Prabhu, Varun V ; Miner, Thomas J ; Lee, Seulki ; Parker, Cassandra S ; Ross, Eric A ; Zhou, Lanlan ; El-Deiry, Wafik S

Gastric adenocarcinoma typically presents with advanced stage when inoperable. Chemotherapy options include non-targeted and toxic agents, leading to poor 5-year patient survival outcomes. Small molecule ONC201/TIC10 (TRAIL-Inducing Compound #10) induces cancer cell death via ClpP-dependent activation of the integrated stress response (ISR) and up-regulation of the TRAIL pathway. We previously found in breast cancer, pancreatic cancer and endometrial cancer that ONC201 primes tumor cells for TRAIL-mediated cell death through ISR-dependent upregulation of ATF4, CHOP and TRAIL death receptor DR5. We investigated the ability of ONC201 to induce apoptosis in gastric adenocarcinoma cells in combination with recombinant human TRAIL (rhTRAIL) or PEGylated trimeric TRAIL (TLY012). AGS (caspase 8-, KRAS-, PIK3CA-mutant, HER2-amplified), SNU-1 (KRAS-, MLH1-mutant, microsatellite unstable), SNU-5 (p53-mutant) and SNU-16 (p53-mutant) gastric adenocarcinoma cells were treated with ONC201 and TRAIL both in cell culture and in vivo. Gastric cancer cells showed synergy following dual therapy with ONC201 and rhTRAIL/TLY012 (combination indices < 0.6 at doses that were non-toxic towards normal fibroblasts). Synergy was observed with increased cells in the sub-G1 phase of the cell cycle with dual ONC201 plus TRAIL therapy. Increased PARP, caspase 8 and caspase 3 cleavage after ONC201 plus TRAIL further documented apoptosis. Increased cell surface expression of DR5 with ONC201 therapy was observed by flow cytometry, and immunoblotting revealed ONC201 upregulation of the ISR, ATF4, and CHOP. We observed downregulation of anti-apoptotic cIAP-1 and XIAP in all cells except AGS, and cFLIP in all cells except SNU-16. We tested the regimen in an organoid model of human gastric cancer, and in murine sub-cutaneous xenografts using AGS and SNU-1 cells. Our results suggest that ONC201 in combination with TRAIL may be an effective and non-toxic option for the treatment of gastric adenocarcinoma by inducing apoptosis via activation of the ISR, increased cell surface expression of DR5 and down-regulation of inhibitors of apoptosis. Our results demonstrate in vivo anti-tumor effects of ONC201 plus TLY012 against gastric cancer that could be further investigated in clinical trials.

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