Synergistic Antitumor Effect of Triptolide and Cisplatin in Cisplatin Resistant Human Bladder Cancer Cells

Ho, Jin‐Nyoung; Byun, Soo-Hwan; Lee, Sangchul; Oh, Jong Jin; Hong, Sung Kyu; Lee, Sang Eun; Yeon, Jae Seung

doi:10.1016/j.juro.2014.09.007

Cited by 35 publications

(21 citation statements)

References 29 publications

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“…Previous data obtained in in vitro cultured cells showed that the Notch pathway upregulates the levels of ERK phosphorylation and GSI treatment could decrease p‐ERK which presented therapeutic potential of targeting γ‐secretase in non‐small cell lung carcinoma . And p‐ERK also can be suppresses by CDDP alone and then inhibit cell proliferation . In the present study, it was also found that p‐ERK protein expression was downregulated by treatment with DAPT and CDDP alone or in combination.…”

Section: Discussionsupporting

confidence: 77%

“…28 And p-ERK also can be suppresses by CDDP alone and then inhibit cell proliferation. 45 In the present study, it was also found that p-ERK protein expression was downregulated by treatment with DAPT and CDDP alone or in combination.…”

supporting

confidence: 73%

“…AKT is a key regulator of survival and apoptosis. In particular caspase‐9 is one of the main initiator caspases in apoptosis and it is phosphorylated by AKT, leading to the inhibition of caspase‐9 cleavage and apoptosis . Thus, inhibiting AKT activity may provide an avenue for cancer prevention and therapy.…”

Section: Discussionmentioning

confidence: 99%

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Notch pathway inhibition using DAPT, a γ‐secretase inhibitor (GSI), enhances the antitumor effect of cisplatin in resistant osteosarcoma

Dai

Deng

Guo

et al. 2018

Molecular Carcinogenesis

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Overcoming platinum drug resistance represents a major clinical challenge in osteosarcoma (OS) treatment. The high rates and patterns of therapeutic failure seen in patients are consistent with a steady accumulation of drug-resistant cancer stem cells (CSCs). Notch signaling is implicated in regulating CSCs and tumor resistance to platinum. Thus, we attempt to investigate whether inhibiting of Notch pathway could sensitize cisplatin (CDDP) to CDDP-resistant OS cells and the underlying molecular mechanisms. OS cell lines resistant to CDDP were treated with DAPT, CDDP or combination, we present evidences that DAPT enhances the cytotoxic effect of CDDP in resistant OS by inhibiting proliferation, resulting in G0/G1 cell-cycle arrest, inducing apoptosis, and reducing motility. In addition, DAPT targeting depletes OS stem cells (OSCs), thus increasing tumor sensitivity to platinum, which indicating that a dual combination targeting both OSCs and the bulk of tumor cells are needed for tumor eradication. We also found that the combination of CDDP and DAPT exhibit additive suppression on phosphorylated AKT and ERK, contributing to the anti-cancer effects. In animal model, this combination therapy inhibits the growth and metastasis of CDDP resistant tumor xenografts in nude mice to a greater extent than treatment with either reagent alone. Based on these results, we conclude that CDDP plus DAPT was able to sensitize CDDP-resistant human OS cells to CDDP by downregulation of Notch signaling. CDDP and DAPT combination treatment may be effective and promising for advanced OS.

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Section: Discussionsupporting

confidence: 77%

supporting

confidence: 73%

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Notch pathway inhibition using DAPT, a γ‐secretase inhibitor (GSI), enhances the antitumor effect of cisplatin in resistant osteosarcoma

Dai

Deng

Guo

et al. 2018

Molecular Carcinogenesis

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“…This ability to block DNA repair has important implications for the anticancer activity of CDDP, which effectiveness has been shown to be enhanced by the combined treatment with triptolide (26). In agreement with that, experimental studies confirmed that low concentrations of triptolide were able to potentiate the CDDP activity in human lung cancer (27) and human bladder CDDP-resistant cells (28).…”

Section: Discussionsupporting

confidence: 64%

Cisplatin Resistance in Osteosarcoma: In vitro Validation of Candidate DNA Repair-Related Therapeutic Targets and Drugs for Tailored Treatments

et al. 2020

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Treatment of high-grade osteosarcoma, the most common malignant tumor of bone, is largely based on administration of cisplatin and other DNA damaging drugs. Altered DNA repair mechanisms may thus significantly impact on either response or resistance to chemotherapy. In this study, by using a panel of human osteosarcoma cell lines, either sensitive or resistant to cisplatin, we assessed the value as candidate therapeutic targets of DNA repair-related factors belonging to the nucleotide excision repair (NER) or base excision repair (BER) pathways, as well as of a group of 18 kinases, which expression was higher in cisplatin-resistant variants compared to their parental cell lines and may be indirectly involved in DNA repair. The causal involvement of these factors in cisplatin resistance of human osteosarcoma cells was validated through gene silencing approaches and in vitro reversal of CDDP resistance. This approach highlighted a subgroup of genes, which value as promising candidate therapeutic targets was further confirmed by protein expression analyses. The in vitro activity of 15 inhibitor drugs against either these genes or their pathways was then analyzed, in order to identify the most active ones in terms of inherent activity and ability to overcome cisplatin resistance. NSC130813 (NERI02; F06) and triptolide, both targeting NER factors, proved to be the two most active agents, without evidence of cross-resistance with cisplatin. Combined in vitro treatments showed that NSC130813 and triptolide, when administered together with cisplatin, were able to improve its efficacy in both drug-sensitive and resistant osteosarcoma cells. This evidence may indicate an interesting therapeutic future option for treatment of osteosarcoma patients who present reduced responsiveness to cisplatin, even if possible effects of additive collateral toxicities must be carefully considered. Moreover, our study also showed that targeting protein kinases belonging to the mitogen-activated protein kinase (MAPK) or fibroblast growth factor receptor (FGFR) pathways might indicate new promising therapeutic perspectives in osteosarcoma, demanding for additional investigation.

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“…For example, cisplatin has been used as an apoptosis inducer in clinical administration for cancer types such as breast, bladder, ovarian, gastric, and cervical. However, abnormalities in caspase deficiencies and Bcl-2 overexpression lead to tumorresistant to cisplatin treatment (Blanc et al, 2000;Cho et al, 2011;Dasari and Bernard Tchounwou, 2014;Ho et al, 2014;Kong et al, 2011;Liu et al, 2012). It is important to develop novel therapeutic strategies to solve the emerging problem of apoptotic resistance.…”

Section: Discussionmentioning

confidence: 99%

Induction of Autophagic Death in Cancer Cells by Agonizing TR3 and Attenuating Akt2 Activity

Wang

Hou

et al. 2015

Chemistry & Biology

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Apoptotic resistance is becoming a significant obstacle for cancer therapy as the majority of treatment takes the route of apoptotic induction. It is of great importance to develop an alternative strategy to induce cancer cell death. We previously reported that autophagic cell death mediated by nuclear receptor TR3 and driven by a chemical agonist, 1-(3,4,5-trihydroxyphenyl)nonan-1-one (THPN), is highly effective in the therapy of melanoma but not any other cancer types. Here, we discovered that the insensitivity of cancer cells to THPN originated from a high cellular Akt2 activity. Akt2 phosphorylation interferes with TR3 export to cytoplasm and targeting to mitochondria, which lead to the autophagic induction. Therefore, the TR3-mediated autophagy could be effectively induced in the otherwise insensitive cells by downregulating Akt2 activity. Highly effective antineoplastic compounds are developed through optimizing the structure of THPN. This study implicates a general strategy for cancer therapy by the induction of autophagic cell death.

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Synergistic Antitumor Effect of Triptolide and Cisplatin in Cisplatin Resistant Human Bladder Cancer Cells

Abstract: Our results suggest that triptolide synergistically enhanced the antitumor effect of cisplatin in cisplatin resistant human bladder cancer cells. Cisplatin and triptolide combination treatment may be effective for advanced bladder cancer.

Cited by 35 publications

References 29 publications

Notch pathway inhibition using DAPT, a γ‐secretase inhibitor (GSI), enhances the antitumor effect of cisplatin in resistant osteosarcoma

Notch pathway inhibition using DAPT, a γ‐secretase inhibitor (GSI), enhances the antitumor effect of cisplatin in resistant osteosarcoma

Cisplatin Resistance in Osteosarcoma: In vitro Validation of Candidate DNA Repair-Related Therapeutic Targets and Drugs for Tailored Treatments

Induction of Autophagic Death in Cancer Cells by Agonizing TR3 and Attenuating Akt2 Activity

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