Proteasome Inhibitor YSY01A Enhances Cisplatin Cytotoxicity in Cisplatin-Resistant Human Ovarian Cancer Cells

Huang, Wei; Zhou, Quan; Yuan, Xia; Zhang, Ge; Ran, Fuxiang; Yang, Huayu; Qiang, Guangliang; Li, Runtao; Cui, Jinshi

doi:10.7150/jca.14519

Cited by 14 publications

(21 citation statements)

References 38 publications

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“…Because the observed effect of combined AA and anti-PD1 therapies was greater than the expected additive effect (as seen in Fig. 3C) we applied the coefficient of drug interaction (CDI) formula (23)(24)(25)(26)(27) to calculate synergy using mean tumor weight measurements. The CDI between high-dose AA and anti-PD1 using the mean tumor weight measurements was 0.63, indicating a significantly synergistic effect (CDI < 0.7).…”

Section: Aa Pretreatment Of Lymphoma Cells Leads To Increased Sensitimentioning

confidence: 99%

High-dose ascorbic acid synergizes with anti-PD1 in a lymphoma mouse model

Luchtel

Bhagat

Pradhan

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

119

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Major efforts are underway to identify agents that can potentiate effects of immune checkpoint inhibition. Here, we show that ascorbic acid (AA) treatment caused genomewide demethylation and enhanced expression of endogenous retroviral elements in lymphoma cells. AA also increased 5-hydroxymethylcytosine (5hmC) levels of CD8+ T cells and enhanced their cytotoxic activity in a lymphoma coculture system. High-dose AA treatment synergized with anti-PD1 therapy in a syngeneic lymphoma mouse model, resulting in marked inhibition of tumor growth compared with either agent alone. Analysis of the intratumoral epigenome revealed increased 5hmC with AA treatment, consistent with in vitro findings. Analysis of the tumor immune microenvironment revealed that AA strikingly increased intratumoral infiltration of CD8+ T cells and macrophages, suggesting enhanced tumor immune recognition. The combination treatment markedly enhanced intratumoral infiltration of macrophages and CD8+ T lymphocytes, granzyme B production by cytotoxic cells (cytotoxic T cells and natural killer cells), and interleukin 12 production by antigen-presenting cells compared with single-agent anti-PD1. These data indicate that AA potentiates anti-PD1 checkpoint inhibition through synergistic mechanisms. The study provides compelling rationale for testing combinations of high-dose AA and anti-PD1 agents in patients with aggressive B cell lymphoma as well as in preclinical models of other malignancies.

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Section: Aa Pretreatment Of Lymphoma Cells Leads To Increased Sensitimentioning

confidence: 99%

High-dose ascorbic acid synergizes with anti-PD1 in a lymphoma mouse model

Luchtel

Bhagat

Pradhan

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

119

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“…The major factor that limits the efficiency of chemotherapy is resistance acquisition (7). Some mechanisms proposed to contribute to resistance include decreased drug capture by cells, increased drug efflux, and increased DNA repair (8). In addition, characteristics such as self-renewal, chemoresistance, anchorage-independent growth, and apoptosis resistance have been associated with drug resistance, cancer progression, and tumor recurrence (9)(10)(11).…”

Section: ' Introductionmentioning

confidence: 99%

Apoptosis-related gene expression can predict the response of ovarian cancer cell lines to treatment with recombinant human TRAIL alone or combined with cisplatin

Braga

Gonçales

Furtado

et al. 2020

Clinics

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The objectives of this study were to determine the sensitivity of ovarian cancer (OC) cell lines (TOV-21G and SKOV-3) to cisplatin and to the recombinant human TRAIL (rhTRAIL), and to evaluate the expression profile of TNFRSF10B, TNFRSF10C, TP53TG5, MDM2, BAX, BCL-2 and CASPASE-8 genes and their participation in the resistance/susceptibility mechanism of these tumor cell lines. METHODS: To determine the IC 50 values associated with Cisplatin and rhTRAIL, inhibition of cell growth was observed using MTT assays in two human OC cell lines (SKOV-3 and TOV-21G). The analysis of gene expression was performed using quantitative real-time polymerase chain reaction (qRT-PCR). RESULTS: Both cell lines had different susceptibility profiles to the tested drugs. In the SKOV-3 cell line, the IC 50 values for cisplatin and for rhTRAIL were 270.83 ug/mL and 196.5 ng/mL, respectively. The same concentrations were used for TOV-21G. Different gene expression profiles were observed in each tested cell line. CASPASE-8 and TNFRSF10B expression levels could predict the response of both the cell lines to rhTRAIL alone or the response to a combination of rhTRAIL and cisplatin. In addition, we observed a relationship between BCL-2 and BAX expression that may be helpful in estimating the proliferation rate of the OC cell lines. CONCLUSION: SKOV-3 and TOV-21G respond differently to cisplatin and rhTRAIL exposure, and expression of CASPASE-8 and TNFRSF10B are good predictors of responses to these treatments.

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“…YSY01A also enhances cisplatin cytotoxicity in cisplatin-resistant ovarian cancer by suppression of NF-κB and STAT3 targeted genes such as bcl-2 (Huang et al, 2016b). However, comparatively few studies have explored the therapeutic efficacy of YSY01A in non-small cell lung carcinoma and little is known about the mechanism by which YSY01A modulates STAT3 signaling cascade.…”

Section: Discussionmentioning

confidence: 99%

Proteasome Inhibitor YSY01A Abrogates Constitutive STAT3 Signaling via Down-regulation of Gp130 and JAK2 in Human A549 Lung Cancer Cells

et al. 2017

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Proteasome inhibition interfering with many cell signaling pathways has been extensively explored as a therapeutic strategy for cancers. Proteasome inhibitor YSY01A is a novel agent that has shown remarkable anti-tumor effects; however, its mechanisms of action are not fully understood. Here we report that YSY01A is capable of suppressing cancer cell survival by induction of apoptosis. Paradoxically, we find that YSY01A abrogates constitutive activation of STAT3 via proteasome-independent degradation of gp130 and JAK2, but not transcriptional regulation, in human A549 non-small cell lung cancer cells. The reduction in gp130 and JAK2 can be restored by co-treatment with 3-methyladenine, an early-stage autophagy lysosome and type I/III PI3K inhibitor. YSY01A also effectively inhibits cancer cell migration and lung xenograft tumor growth with little adverse effect on animals. Thus, our findings suggest that YSY01A represents a promising candidate for further development of novel anticancer therapeutics targeting the proteasome.

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Proteasome Inhibitor YSY01A Enhances Cisplatin Cytotoxicity in Cisplatin-Resistant Human Ovarian Cancer Cells

Cited by 14 publications

References 38 publications

High-dose ascorbic acid synergizes with anti-PD1 in a lymphoma mouse model

High-dose ascorbic acid synergizes with anti-PD1 in a lymphoma mouse model

Apoptosis-related gene expression can predict the response of ovarian cancer cell lines to treatment with recombinant human TRAIL alone or combined with cisplatin

Proteasome Inhibitor YSY01A Abrogates Constitutive STAT3 Signaling via Down-regulation of Gp130 and JAK2 in Human A549 Lung Cancer Cells

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