Scientific Reports
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2024
·Vol. 14
·期 1
·1-15
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IF 3.8
Chen Linli,Guo Xiaojing,Lin Wen,Huang Yingying,Zhuang Suling,Li Qianfeng,Xu Jianhua,Ye Shengnan
Lytic induction therapy was devised to selectively combat malignancies associated with Epstein–Barr virus (EBV) by triggering viral reactivation from latency. At present, the major challenges of lytic induction therapy are to maximize reactivating efficiencies and meanwhile minimize infectious virion production. C210, a novel curcumin derivative with potent Hsp90 inhibitory activity, was explored for EBV-reactivating and virion-producing effects in EBV-positive nasopharyngeal carcinoma (NPC) and gastric carcinoma (GC) cell lines. And the molecular mechanisms underlying these effects were determined. Follow C210 treatment, EBV lytic RNAs and proteins were upregulated, but infectious virions were not produced. Knockdown of heat shock protein 90 (Hsp90) induced expression of lytic RNAs and proteins, and diminished C210-driven EBV lytic induction. Pretreatment with an X box binding protein 1 (XBP1) inhibitor reduced C210-induced EBV lytic RNA. Furthermore, we demonstrated that C210 inhibited the binding of Hsp90 with its clients, signal transducer and activator of transcription 3 (STAT3) and xeroderma pigmentosum group B-complementing protein (XPB), which subsequently promoted their proteasomal degradation. Degradation of STAT3 by C210 enhanced the EBV-reactivating and anticancer capacity of suberoylanilide hydroxamic acid (SAHA). Depletion of XPB blocked SAHA-induced expression of late viral genes and production of infectious virions. These results elucidate a novel Hsp90 inhibitor targeting EBV lytic phase and extend the research on lytic induction strategy, which may offer reference value in the treatment of EBV-positive malignancies.
研究领域:
肿瘤学
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病毒学
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分子生物学
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药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
DRUG RESISTANCE UPDATES
·
2025
·
IF 21.7
Muhammad Zubair Saleem,Ruyi Huang,Yingying Huang,Xin Guo,Yang Liu,Miao Gao,Yinjuan Fan,Zhe-Sheng Chen,Zun-Fu Ke,Shengnan Ye,Jianhua Xu
Aims TRAP1 is involved in metabolic reprogramming and promotes drug resistance. We aimed to explore whether a novel HSP90 inhibitor, C210, overcomes doxorubicin (DOX) resistance of quiescent breast cancer cells by targeting TRAP1. Methods Breast cancer cells were induced to quiescence by hypoxia and low glucose. The relationship of cell metabolism with HSP90 and TRAP1 was investigated by Western blotting, ECAR, OCR, mitochondrial complex activity, and proteomic analysis. The targets of C210 and their functions were analyzed by SPR and immunoprecipitation. The antitumor effect in vivo was investigated with mouse tumor model. Results In hypoxia and glucose deprivation, breast cancer cells exhibited elevated TRAP1 and an OXPHOS-enhanced quiescent phenotype. These cells were highly resistant to DOX but more sensitive to C210. C210 disrupted TRAP1's interaction with OXPHOS-associated client proteins, prompting proteasome-dependent degradation of these proteins, thereby reducing OCR, mitochondrial ATP production and resulting in selective elimination of the quiescent cancer cells by inducing mitochondrial apoptosis which could be reversed by exogenous ATP. Moreover, C210 targeted glycolytic, amino acid, and β-oxidation-associated proteome. C210 demonstrated promising in vivo anticancer efficacy which was particularly related to OXPHOS inhibition. Conclusions C210 eliminates DOX-resistant quiescent breast cancer cells by targeting TRAP1-dependent bioenergetics.
研究领域:
肿瘤学
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分子生物学
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药物研发
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产品关联
DOI
PubMed
高影响因子
Pharmaceutics
·
2023
·Vol. 15
·期 5
·1546
·
IF 5.4
Xin Guo,Min Wu,Yanping Deng,Yan Liu,Yanpeng Liu,Jianhua Xu
The poor bioavailability of curcumin and its derivatives limits their antitumor efficacy and clinical translation. Although curcumin derivative C210 has more potent antitumor activity than curcumin, it has a similar deficiency to curcumin. In order to improve its bioavailability and accordingly enhance its antitumor activity in vivo, we developed a redox-responsive lipidic prodrug nano-delivery system of C210. Briefly, we synthesized three conjugates of C210 and oleyl alcohol (OA) via different linkages containing single sulfur/disulfide/carbon bonds and prepared their nanoparticles using a nanoprecipitation method. The prodrugs required only a very small amount of DSPE-PEG2000 as a stabilizer to self-assemble in aqueous solution to form nanoparticles (NPs) with a high drug loading capacity (~50%). Among them, the prodrug (single sulfur bond) nanoparticles (C210-S-OA NPs) were the most sensitive to the intracellular redox level of cancer cells; therefore, they could rapidly release C210 in cancer cells and thus had the strongest cytotoxicity to cancer cells. Furthermore, C210-S-OA NPs exerted a dramatic improvement in its pharmacokinetic behavior; that is, the area under the curve (AUC), mean retention time and accumulation in tumor tissue were 10, 7 and 3 folds that of free C210, respectively. Thus, C210-S-OA NPs exhibited the strongest antitumor activity in vivo than C210 or other prodrug NPs in mouse models of breast cancer and liver cancer. The results demonstrated that the novel prodrug self-assembled redox-responsive nano-delivery platform was able to improve the bioavailability and antitumor activity of curcumin derivative C210, which provides a basis for further clinical applications of curcumin and its derivatives.Keywords:curcumin derivatives;redox-responsive;self-assemble;prodrug;bioavailability;antitumor
研究领域:
药学
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纳米技术
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肿瘤学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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