Effects of lobaplatin as a single agent and in combination with TRAIL on the growth of triple-negative p53-mutated breast cancers in vitro

Engel, Jörg B.; Martens, Theresa; Hahne, Jens C.; Häusler, Sebastian; Krockenberger, Mathias; Segerer, Sabine; Djakovic, A.; Meyer, Susanne; Dietl, Johannes; Wischhusen, Jörg; Hönig, Arnd

doi:10.1097/cad.0b013e32834fb8ce

Cited by 21 publications

(10 citation statements)

References 39 publications

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“…More encouraging, Hunter and coworkers have reported that TRAIL can kill small cell lung cancer cells by inducing caspase-independent mechanisms of cell death in synergy with paclitaxel [35]. Independently, platinum compounds in combination with TRAIL were found to be effective against breast cancer cells by inducing programmed necrosis (although to a lesser extent) in addition to apoptosis [36]. Finally, Katz and colleagues have described that malignant pleural mesothelioma cells are killed by caspase-independent mechanisms after application of TRAIL in combination with sorafenib, and even find promising evidence of therapeutic efficacy in a xenograft mouse model [37], in summary corroborating our data on the synergistic action of TRAIL/zVAD/CHX and chemotherapy in the programmed necrosis of tumor cell lines.…”

Section: Discussionmentioning

confidence: 99%

TRAIL-induced programmed necrosis as a novel approach to eliminate tumor cells

et al. 2014

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BackgroundThe cytokine TRAIL represents one of the most promising candidates for the apoptotic elimination of tumor cells, either alone or in combination therapies. However, its efficacy is often limited by intrinsic or acquired resistance of tumor cells to apoptosis. Programmed necrosis is an alternative, molecularly distinct mode of programmed cell death that is elicited by TRAIL under conditions when the classical apoptosis machinery fails or is actively inhibited. The potential of TRAIL-induced programmed necrosis in tumor therapy is, however, almost completely uncharacterized. We therefore investigated its impact on a panel of tumor cell lines of wide-ranging origin.MethodsCell death/viability was measured by flow cytometry/determination of intracellular ATP levels/crystal violet staining. Cell surface expression of TRAIL receptors was detected by flow cytometry, expression of proteins by Western blot. Ceramide levels were quantified by high-performance thin layer chromatography and densitometric analysis, clonogenic survival of cells was determined by crystal violet staining or by soft agarose cloning.ResultsTRAIL-induced programmed necrosis killed eight out of 14 tumor cell lines. Clonogenic survival was reduced in all sensitive and even one resistant cell lines tested. TRAIL synergized with chemotherapeutics in killing tumor cell lines by programmed necrosis, enhancing their effect in eight out of 10 tested tumor cell lines and in 41 out of 80 chemotherapeutic/TRAIL combinations. Susceptibility/resistance of the investigated tumor cell lines to programmed necrosis seems to primarily depend on expression of the pro-necrotic kinase RIPK3 rather than the related kinase RIPK1 or cell surface expression of TRAIL receptors. Furthermore, interference with production of the lipid ceramide protected all tested tumor cell lines.ConclusionsOur study provides evidence that TRAIL-induced programmed necrosis represents a feasible approach for the elimination of tumor cells, and that this treatment may represent a promising new option for the future development of combination therapies. Our data also suggest that RIPK3 expression may serve as a potential predictive marker for the sensitivity of tumor cells to programmed necrosis and extend the previously established role of ceramide as a key mediator of death receptor-induced programmed necrosis (and thus as a potential target for future therapies) also to the tumor cell lines examined here.

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Section: Discussionmentioning

confidence: 99%

TRAIL-induced programmed necrosis as a novel approach to eliminate tumor cells

et al. 2014

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“…To assess the cytotoxic effect of those drugs, a sulforhodamine-B assay was used as described by Skeehan et al (Engel et al, 2012;Skehan et al, 1990;Xie et al, 2012).In Brief, cells were seeded at appropriate densities into 96-well microtiter plates and allowed to attach for 24h. Then the drugs dissolved in growth medium were added at appropriate concentrations for 72h.…”

Section: Measurement Of Cytotoxicitymentioning

confidence: 99%

Preclinical Activity of Lobaplatin as a Single Agent and in Combination with Taxanes for Ovarian Carcinoma Cells

Sun¹,

Lou²,

Sui³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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Lobaplatin, one of the third -generation platinum compounds, has shown encouraging anticancer activity in a variety of tumor types. However, the efficacy of lobaplatin in ovarian cancer has not been systemically evaluated. In this study, lobaplatin as a single agent and in combination with taxanes was investigated in -vitro and in an in vitro model of ovarian carcinoma. Using the sulforhodamine B (SRB) assay, the cytotoxic effects of lobaplatin alone and in combination with taxanes were compared with cisplatin and carboplatin in seven ovarian cancer cell lines. In addition, in -vitro antitumor activities were evaluated with cisplatin -sensitive and cisplatin -resistant human ovarian cancer xenografts in nude mice. The cytotoxicity of lobaplatin was similar to or higher than that of cisplatin and carboplatin, with IC 50 values from 0.9 to 13.8 µmol/L in a variety of ovarian cancer cells. The combination of lobaplatin with docetaxel yielded enhanced cytotoxic activity in vitro. In addition, in platinum -sensitive ovarian cancer xenografts, lobaplatin alone showed similar antitumor activity to cisplatin and carboplatin. Furthermore, lobaplatin alone or in combination with docetaxel exhibited significant activity in platinum -resistant ovarian cancer xenografts. These results indicate that the use of lobaplatin alone or in combination with docetaxel might be a rational and novel therapeutic strategy for ovarian cancer. Further clinical development of lobaplatin is clearly warranted.

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“…Necroptosis might act as an alternative pathway to initiate cell death when apoptosis is restrained. Since RIP3 serves as a critical regulator of necroptosis, silencing RIP3 causes cancer cells to develop resistance to 5-FU [59,60], cisplatin [61][62][63], camptothecin and etoposide and the activation of key regulators in necroptotic pathway can increase the sensitivity of cells to chemotherapy drugs [5]. Here, we demonstrated that administration of TCN combination with cisplatin signi cantly increased the chemotherapeutic sensitivity of cancer cells in vivo.…”

Section: Discussionmentioning

confidence: 66%

RIP3 mediates TCN-induced necroptosis through activating mitochondrial metabolism and ROS production in apoptosis-resistant cancer cells

Zhao¹,

Quan²,

Tan³

et al. 2020

Preprint

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Background: Resisting cell death is one of the hallmarks of cancer. Necroptosis is a form of non-caspase dependent necrotic cell death mediated by receptor-interacting protein kinase-1/3 (RIP1/3), which represents another mode of programmed cell death besides apoptosis. Growing evidence supports that RIP3 has emerged as a critical regulator of necroptosis and can be activated by several stimuli to trigger necroptotic cell death in a RIP1-independent manner. RIP3 also acts as an energy metabolism regulator associated with switching cell death from apoptosis to necroptosis. Natural products provide a unique source for the discovery of innovative leading compounds and drugs, which exhibits promising anticancer activities through inducing cell death and enhancing chemotherapeutic sensitivity. Trichothecin (TCN) is a sesquiterpenoid originating from an endophytic fungus of the herbal plant Maytenus hookeri Loes and shows potent anti-tumor bioactivity. However, the underlying mechanism is not fully understood.Methods: Cell permeability assay and transmission electron microscopy were applied to identify the death pattern induced by TCN in apoptotic-resistant cancer cells. We used Seahorse extracellular flux analyzer to examine the cellular oxygen consumption rate (OCR) and flow cytometry to detect mitochondrial reactive oxygen species (ROS) content. Xenograft animal experiment was performed to assess the effect of TCN synergized with cisplatin to enhance chemotherapeutic sensitivity of tumor cells. Results: Our current findings revealed that RIP3 mediated TCN-induced necroptosis through activating mitochondria energy metabolism and ROS production in apoptotic-resistant cancer cells. RIP3 might be involved in sensitizing tumor cells to chemotherapy induced by TCN. Conclusions: Activating RIP3 to induce necroptosis through reprogramming mitochondrial energy metabolism and ROS production contributes to the anti-tumor activity of TCN. Moreover, TCN could be exploited for therapeutic gain through up-regulating RIP3 to sensitize cancer chemotherapy.

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Effects of lobaplatin as a single agent and in combination with TRAIL on the growth of triple-negative p53-mutated breast cancers in vitro

Cited by 21 publications

References 39 publications

TRAIL-induced programmed necrosis as a novel approach to eliminate tumor cells

TRAIL-induced programmed necrosis as a novel approach to eliminate tumor cells

Preclinical Activity of Lobaplatin as a Single Agent and in Combination with Taxanes for Ovarian Carcinoma Cells

RIP3 mediates TCN-induced necroptosis through activating mitochondrial metabolism and ROS production in apoptosis-resistant cancer cells

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