Enhancing apoptosis in TRAIL-resistant cancer cells using fundamental response rules

Piras, Vincent; Hayashi, Kentaro; Tomita, Masaru; Selvarajoo, Kumar

doi:10.1038/srep00144

Cited by 31 publications

(34 citation statements)

References 54 publications

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“…To tackle this challenge the cancer field would benefit from detailed characterization of the genetic and epigenetic makeup of patient-derived tumors to identify defects in cell proliferation and death pathways[79]. Computational modeling could prove invaluable to help collate and interpret huge datasets, finding novel targets that might enhance apoptosis in TRAIL-resistant populations[80]. To complement this approach, preclinical studies should focus on using primary patient-derived cell lines as opposed to established cancer cell lines.…”

Section: Concluding Remarks and Future Perspectivesmentioning

confidence: 99%

TRAIL on trial: preclinical advances in cancer therapy

Stuckey

Shah

2013

Trends in Molecular Medicine

257

209

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TNF-related apoptosis-inducing ligand, or TRAIL, is a promising anti-cancer agent as it can induce apoptosis in a wide range of cancers whilst generally sparing non-malignant cells. However, the translation of TRAIL into the clinic has been confounded by its short half-life, inadequate delivery methods and TRAIL-resistant cancer cell populations. In this review we discuss how TRAIL has been functionalized to diversify its traditional tumor-killing role and novel strategies to facilitate its effective deployment in preclinical cancer models. The successes and failures of the most recent clinical trials using TRAIL agonists are discussed and we provide a perspective for improving its clinical implementation.

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Section: Concluding Remarks and Future Perspectivesmentioning

confidence: 99%

TRAIL on trial: preclinical advances in cancer therapy

Stuckey

Shah

2013

Trends in Molecular Medicine

257

209

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“…3C suggest that MT-6 activates cleavage of caspase-8 and -9, representing extrinsic (death receptor) and intrinsic (mitochondria) pathways of apoptosis, respectively. Previous studies have indicated that TRAIL-induced cell death signaling is related to both extrinsic and intrinsic apoptotic pathways, and may be a promising therapeutic pathway for targeting by single agents or combined treatment with conventional chemotherapies2930. To delineate the mechanism of MT-6–induced cell death, we further examined the levels of death receptors for pro-apoptotic signaling, such as transmembrane death receptors belonging to the tumor necrosis factor receptor (TNFR) superfamily.…”

Section: Resultsmentioning

confidence: 99%

The apoptotic mechanisms of MT-6, a mitotic arrest inducer, in human ovarian cancer cells

Chen

Kuo

Hsu

et al. 2017

Sci Rep

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Patients with ovarian cancer are typically diagnosed at an advanced stage, resulting in poor prognosis since there are currently no effective early-detection screening tests for women at average-risk for ovarian cancer. Here, we investigated the effects of MT-6, a derivative of moscatilin, in ovarian cancer cells. Our investigation showed that MT-6 inhibited the proliferation and viability of ovarian cancer cells with submicromolar IC 50 values. MT-6-treated SKOV3 cells showed significant cell cycle arrest at G2/M phase, followed by an increase in the proportion of cells in a sub-G1 phase. In addition, MT-6 induced a concentration-dependent increase in mitotic markers, mitotic kinases, cell cycle regulators of G2/M transition, and apoptosis-related markers in ovarian cancer cells. MT-6 treatment also induced mitochondrial membrane potential loss, JNK activation, and DR5 expression. Cotreatment of cells with the JNK inhibitor SP600125 considerably attenuated MT-6-induced apoptosis, mitochondria membrane potential loss, DR5 upregulation, and suppression of cell viability. MT-6 also inhibited tumor growth in an SKOV3 xenograft model without significant body weight loss. Together, our findings suggest that MT-6 is a potent anticancer agent with tumor-suppressive activity in vitro and in vivo that could be further investigated for ovarian cancer therapy in the future.Among malignant gynecological tumors, patients with ovarian cancer have a high mortality rate owing to late stage diagnosis 1 . In addition to debulking surgery, the standard treatment for ovarian cancer is platinum-based chemotherapy in combination with taxane cytotoxic drugs, but a majority of these patients ultimately relapse within 2 years 2 . Therefore, prolonged courses of chemotherapy or better therapeutic options need to be continuously investigated. Antimitotic agents, which produce significant cytotoxicity, have been used effectively in the clinic for decades in patients with a variety of malignancies, including breast cancer, ovarian cancer, and lung cancer 3,4 . Although current trends of drug development for cancer treatment emphasize target-oriented approaches to enhance specificity so as to reduce unwanted side effects, novel antimitotic drugs still retain significant clinical value and have yielded promising outcomes [5][6][7] . During the cell cycle, progression from G2 to M phase requires activation of the Cdk1/cyclin B1 complex, which is controlled by phosphorylation at different sites of Cdk1 8,9 . Antimitotic agents usually target microtubule dynamics and cell-cycle regulatory proteins, whose main function is to properly coordinate cell division in mammalian cells. Consequently, antimitotic drugs cause cell cycle dysregulation (mitotic arrest) followed by aberrant division and cell death 10 . Apoptosis, the best-known form of programmed cell death, mainly involves activation of a cascade of caspase that is triggered by the extrinsic (death receptor) or intrinsic (mitochondrial) apoptotic pathways and leads to characteristic biochemic...

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“…Some studies showed that the absence of FADD leads to partial TRAIL-resistance and concluded that FADD is necessary for TRAIL-induced apoptosis by the death receptors DR4 and DR5 (74,75). Other groups showed that the induction of apoptosis by TRAIL is independent of FADD in different cell lines (73,76,77). Additionally, FADD was described as a negative regulator of the transcription factor NF-κB (nuclear factor κ-light chain-enhancer of activated B-cells), which promotes cell survival and tumour invasiveness of fibrosarcoma cells (78,79).…”

Section: Discussionmentioning

confidence: 99%

Effects of TRAIL and taurolidine on apoptosis and proliferation in human rhabdomyosarcoma, leiomyosarcoma and epithelioid cell sarcoma

Karlisch¹,

Harati²,

Chromik³

et al. 2013

International Journal of Oncology

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Soft tissue sarcomas (STS) are a heterogeneous group of malignant tumours representing 1% of all malignancies in adults. Therapy for STS should be individualised and multimodal, but complete surgical resection with clear margins remains the mainstay of therapy. Disseminated soft tissue sarcoma still represents a therapeutic dilemma. Commonly used chemotherapeutic agents such as doxorubicin and ifosfamide have proven to be effective in fewer than 30% in these cases. Therefore, we tested the apoptotic and anti-proliferative in vitro effects of TNF-related apoptosis-inducing ligand (TRAIL) and taurolidine (TRD) on rhabdomyosarcoma (A-204), leiomyosarcoma (SK-LMS-1) and epithelioid cell sarcoma (VA-ES-BJ) cell lines. Viability, apoptosis and necrosis were quantified by FACS analysis (propidium iodide/Annexin V staining). Gene expression was analysed by DNA microarrays and the results validated for selected genes by rtPCR. Protein level changes were documented by western blot analysis. Cell proliferation was analysed by BrdU ELISA assay. The single substances TRAIL and TRD significantly induced apoptotic cell death and decreased proliferation in rhabdomyosarcoma and epithelioid cell sarcoma cells. The combined use of TRAIL and TRD resulted in a synergistic apoptotic effect in all three cell lines, especially in rhabdomyosarcoma cells leaving 18% viable cells after 48 h of incubation (p<0.05). Analysis of the differentially regulated genes revealed that TRD and TRAIL influence apoptotic pathways, including the TNF-receptor associated and the mitochondrial pathway. Microarray analysis revealed remarkable expression changes in a variety of genes, which are involved in different apoptotic pathways and cross talk to other pathways at multiple levels. This in vitro study demonstrates that TRAIL and TRD synergise in inducing apoptosis and inhibiting proliferation in different human STS cell lines. Effects on gene expression differ relevantly in the sarcoma entities. These results provide experimental support for in vivo trials assessing the effect of TRAIL and TRD in STS and sustain the approach of individualized therapy.

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Enhancing apoptosis in TRAIL-resistant cancer cells using fundamental response rules

Cited by 31 publications

References 54 publications

TRAIL on trial: preclinical advances in cancer therapy

TRAIL on trial: preclinical advances in cancer therapy

The apoptotic mechanisms of MT-6, a mitotic arrest inducer, in human ovarian cancer cells

Effects of TRAIL and taurolidine on apoptosis and proliferation in human rhabdomyosarcoma, leiomyosarcoma and epithelioid cell sarcoma

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