Synergistic Antitumor Activity of Gemcitabine and ABT-737 <i>In Vitro and In Vivo</i> through Disrupting the Interaction of USP9X and Mcl-1

Zhang, Chong; Cai, Tianyu; Zhu, Hong; Yang, Liuqing; Jiang, Hai; Dong, Xiaowu; Hu, Yongzhou; Lin, Nengming; He, Qiaojun; Yang, Bo

doi:10.1158/1535-7163.mct-10-1091

Cited by 50 publications

(41 citation statements)

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“…In our study, decreased XIAP expression was detected in A549 cells treated with chamaejasmenin B, indicating that apoptosis suppression was impaired. Mcl-1 is an essential modulator of survival during development and maintenance in a variety of cell lineages and is a key regulator of apoptosis after DNA damage [31,32] . Our data showed that chamaejasmenin B-induced apoptosis was accompanied by a large decrease in Mcl-1 protein.…”

Section: Discussionmentioning

confidence: 99%

In vitro anti-cancer activity of chamaejasmenin B and neochamaejasmin C isolated from the root of Stellera chamaejasme L

et al. 2012

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Aim: To examine the anti-cancer effects of chamaejasmenin B and neochamaejasmin C, two biflavonones isolated from the root of Stellera chamaejasme L (known as the traditional Chinese herb Rui Xiang Lang Du) in vitro. Methods: Human liver carcinoma cell lines (HepG2 and SMMC-7721), a human non-small cell lung cancer cell line (A549), human osteosarcoma cell lines (MG63, U2OS, and KHOS), a human colon cancer cell line (HCT-116) and a human cervical cancer cell line (HeLa) were used. The anti-proliferative effects of the compounds were measured using SRB cytotoxicity assay. DNA damage was detected by immunofluorescence and Western blotting. Apoptosis and cell cycle distribution were assessed using flow cytometry analysis. The expression of the related proteins was examined with Western blotting analysis. Results: Both chamaejasmenin B and neochamaejasmin C exerted potent anti-proliferative effects in the 8 human solid tumor cell lines. Chamaejasmenin B (the IC 50 values ranged from 1.08 to 10.8 μmol/L) was slightly more potent than neochamaejasmin C (the IC 50 values ranged from 3.07 to 15.97 μmol/L). In the most sensitive A549 and KHOS cells, the mechanisms underlying the anti-proliferative effects were characterized. The two compounds induced prominent expression of the DNA damage marker γ-H2AX as well as apoptosis. Furthermore, treatment of the cells with the two compounds caused prominent G 0 /G 1 phase arrest. Conclusion: Chamaejasmenin B and neochamaejasmin C are potential anti-proliferative agents in 8 human solid tumor cell lines in vitro via inducing cell cycle arrest, apoptosis and DNA damage.

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Section: Discussionmentioning

confidence: 99%

In vitro anti-cancer activity of chamaejasmenin B and neochamaejasmin C isolated from the root of Stellera chamaejasme L

et al. 2012

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“…It has been reported that high levels of Mcl-1 may confer resistance to ABT-737 in several solid tumors (17). Thus, the present study examined the involvement of Mcl-1 in nedaplatin and ABT-737 combination treatment.…”

Section: Combination Of Nedaplatin and Abt-737 Promoted The Degradatimentioning

confidence: 92%

“…Thus, it was hypothesized that low expression of Mcl-1 contributed to the synergistic effect in cancer cell lines. As in all proteins, the equilibrium between production and degradation determines the protein level of Mcl-1, and the stability of Mcl-1 could be critically important in numerous physiologic and pathologic situations (17). Firstly, it was postulated that the synergistic reduction of Mcl-1 protein by nedaplatin plus ABT-737 was the result of transcriptional inhibition.…”

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confidence: 99%

Nedaplatin enhanced apoptotic effects of ABT-737 in human cancer cells via Mcl-1 inhibition

Zhang

Weng

et al. 2016

Oncology Letters

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Abstract. Platinum compounds, such as cisplatin, carboplatin, oxaliplatin and nedaplatin, are widely used to treat a number of solid malignancies. Nedaplatin is a second-generation platinum complex, based on its pronounced anti-cancer activities against several solid tumors being equivalent to that of cisplatin, but with lower nephrotoxicity. In this context, the present study aimed to investigate the potential anti-cancer effect by combining nedaplatin with ABT-737. It was found that nedaplatin greatly increased ABT-737-mediated apoptosis in A549 and 95-D cells, accompanied by enhanced cleavage of poly(ADP-ribose) polymerase and caspase-3. In addition, this enhancement was also paralleled by cytochrome c release and dissipation of mitochondrial membrane potential. Additional mechanistic investigations revealed that nedaplatin plus ABT-737 exerted a synergistic effect on cancer cells through their ability to accelerate the degradation of Mcl-1. The present study has revealed nedaplatin as a pertinent sensitizer to ABT-737, which opens up new avenues for this promising BH3-mimetic molecule in the clinic. IntroductionNedaplatin, a platinum derivative synthesized to overcome problems of cisplatin resistance, was developed by Shionogi Pharmaceutical Company in 1983 with the aim to provide a treatment with effectiveness similar to cisplatin, but with less nephrotoxicity and gastrointestinal toxicities (1). Nedaplatin produces promising response rates in clinical trials as a monotherapy for the treatment of squamous cell carcinoma of the uterus, cervix, head and neck, ovary, lung and esophagus (2-4). Nedaplatin exerts anti-tumor effects following uptake into tumor cells by binding to DNA bases and inhibiting DNA replication, similar to cisplatin and carboplatin (5). However, the ability of cancer cells to become resistant to nedaplatin remains a notable obstacle to successful chemotherapy; resistance of numerous species of cancer cells to nedaplatin can be reversed by combining with chemotherapeutic agents, including 5-fluorouracil, docetaxel and vindesine (6-8). The identification of new chemotherapy regimens incorporating nedaplatin with other chemotherapeutic agents can enhance the knowledge of nedaplatin resistance and support the development of nedaplatin-based approaches to cancer therapy.The B-cell lymphoma 2 (Bcl-2) family members serve as primary regulators of apoptosis and include both pro-and anti-apoptotic molecules (9). Overexpression of anti-apoptotic Bcl-2 family proteins has been associated with chemotherapy resistance in multiple human cancers (10). Myeloid cell leukemia 1 (Mcl-1), an anti-apoptotic protein in the Bcl-2 family, is frequently observed in numerous tumor types and contributes to chemotherapeutic resistance (11).ABT-737 is a small molecule inhibitor of Bcl-2 family proteins. It can bind Bcl-2 and B-cell lymphoma-extra large (Bcl-xL) with high affinity. ABT-737 has shown single agent and combination therapy efficacy against multiple myeloma, acute myeloid leukemia, lymphoma and solid tumor...

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“…Increased USP9X expression should correlate with increased MCL1 protein in tumors and is expected to have a survival advantage. Interestingly, it was shown that inhibiting USP9X to decrease MCL1 potentiates ABT-737 [95,96], further suggesting its role in determining ABT-737 (and navitoclax) sensitivity.…”

Section: Future Directions In Developing Biomarkers Of Response To Anmentioning

confidence: 99%

Biomarkers of Therapeutic Response to BCL2 Antagonists in Cancer

2012

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Cancer cells persist by resisting programmed cell death or apoptosis. In particular, an imbalance of proteins that regulate apoptosis leads to lack of response to apoptotic stimuli. Thus, restoring the ability of cancer cells to undergo apoptosis is highly desirable. One apoptosis pathway, the intrinsic pathway, involves perturbation of the mitochondria. The major players of this pathway are the members of the B cell CLL/lymphoma 2 (BCL2) family. Currently, three BCL2 antagonists are in clinical trials for cancer treatment. While these antagonists show various specificity and potency, the development of companion diagnostics is crucial for developing these compounds into viable cancer treatments. In this review we describe predictive and pharmacodynamic biomarkers for these agents. Future directions on biomarker development for this class of antagonist are also discussed.

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Synergistic Antitumor Activity of Gemcitabine and ABT-737 In Vitro and In Vivo through Disrupting the Interaction of USP9X and Mcl-1

Cited by 50 publications

References 48 publications

In vitro anti-cancer activity of chamaejasmenin B and neochamaejasmin C isolated from the root of Stellera chamaejasme L

In vitro anti-cancer activity of chamaejasmenin B and neochamaejasmin C isolated from the root of Stellera chamaejasme L

Nedaplatin enhanced apoptotic effects of ABT-737 in human cancer cells via Mcl-1 inhibition

Biomarkers of Therapeutic Response to BCL2 Antagonists in Cancer

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