Translational Oncology
·
2021
·
IF 4.243
Qiuli Wang,Dong Liang,Peng Shen,Yang Yu,Yuan Yan,Wei You
Previous study has confirmed that hsa_circ_0092276 is highly expressed in doxorubicin (DOX)-resistant breast cancer cells, indicating that hsa_circ_0092276 may be involved in regulating the chemotherapy resistance of breast cancer. Here we attempted to investigate the biological role of hsa_circ_0092276 in breast cancer. We first constructed DOX-resistant breast cancer cells (MCF-7/DOX and MDA-MB-468/DOX). The 50% inhibiting concentration of MCF-7/DOX and MDA-MB-468/DOX cells was significantly higher than that of their parental breast cancer cells, MCF-7 and MDA-MB-46. MCF-7/DOX and MDA-MB-468/DOX cells also exhibited an up-regulation of drug resistance-related protein MDR1. Compared with MCF-7 and MDA-MB-46 cells, hsa_circ_0092276 was highly expressed in MCF-7/DOX and MDA-MB-468/DOX cells. Hsa_circ_0092276 overexpression enhanced proliferation and the expression of LC3-II/LC3-I and Beclin-1, and repressed apoptosis of breast cancer cells. The effect of hsa_circ_0092276 up-regulation on breast cancer cells was abolished by 3-methyladenine (autophagy inhibitor). Hsa_circ_0092276 modulated autophagy-related gene 7 (ATG7) expression via sponging miR-384. Hsa_circ_0092276 up-regulation promoted autophagy and proliferation, and repressed apoptosis of breast cancer cells, which was abolished by miR-384 overexpression or ATG7 knockdown. In addition, LV-circ_0092276 transfected MCF-7 cell transplantation promoted autophagy and tumor growth of breast cancer in mice. In conclusion, our data demonstrate that hsa_circ_0092276 promotes autophagy and DOX resistance in breast cancer by regulating miR-348/ATG7 axis. Thus, this article highlights a novel competing endogenous RNA circuitry involved in DOX resistance in breast cancer.
研究领域:
肿瘤学
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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
Frontiers in Pharmacology
·
2023
·
IF 5.6
Chen Zhenzhen,Liu Zhihong,Zhang Qian,Huang Sheng,Zhang Zaizhong,Feng Xianquan,Zeng Lingjun,Lin Ding,Wang Lie,Song Hongtao
Drug resistance is a huge hurdle in tumor therapy. Tumor hypoxia contributes to chemotherapy resistance by inducing the hypoxia-inducible factor-1α (HIF-1α) pathway. To reduce tumor hypoxia, novel approaches have been devised, providing significant importance to reverse therapeutic resistance and improve the effectiveness of antitumor therapies. Herein, the nanosystem of bovine serum albumin (BSA)-templated manganese dioxide (MnO2) nanoparticles (BSA/MnO2 NPs) loaded with doxorubicin (DOX) (DOX-BSA/MnO2 NPs) developed in our previous report was further explored for their physicochemical properties and capacity to reverse DOX resistance because of their excellent photothermal and tumor microenvironment (TME) response effects. The DOX-BSA/MnO2 NPs showed good biocompatibility and hemocompatibility. Meanwhile, DOX-BSA/MnO2 NPs could greatly affect DOX pharmacokinetic properties, with prolonged circulation time and reduced cardiotoxicity, besides enhancing accumulation at tumor sites. DOX-BSA/MnO2 NPs can interact with H2O2 and H+ in TME to form oxygen and exhibit excellent photothermal effect to further alleviate hypoxia due to MnO2, reversing DOX resistance by down-regulating HIF-1α expression and significantly improving the antitumor efficiency in DOX-resistant human breast carcinoma cell line (MCF-7/ADR) tumor model. The hypoxia-ameliorated photothermal MnO2 platform is a promising strategy for revering DOX resistance.
研究领域:
癌症治疗
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纳米技术
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药理学
✓ 已验证
DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2024
·
IF 6.7
Xuan Jiang,Manli Wang,Guoliang Cui,Yuanyuan Wu,Zhonghong Wei,Suyun Yu,Aiyun Wang,Wei Zou,Yanhong Pan,Xiaoman Li,Yin Lu
Background Tetramethylpyrazine (TMP), a key bioactive constituent derived from Ligusticum wallichii Franchat , has demonstrated efficacy in mitigating multidrug resistance (MDR) in human breast cancer (BC) cells. However, the precise mechanisms underlying its action remain poorly understood. Purpose Cancer stem cells (CSCs) are widely recognized as the primary contributors to MDR. This investigation seeks to elucidate the role and mechanisms through which TMP counteracts MDR by attenuating CSC-like characteristics. Methods Various assays, including flow cytometry, sphere formation, and Western blotting, were employed to evaluate TMP's effects on breast cancer stem cell (BCSC)-like phenotypes in vitro. In vivo , extreme limiting dilution assays and immunohistochemistry (IHC) were executed to assess the impacts of TMP on BCSC frequency and the levels of stemness markers. Mechanistically, RNA sequencing was performed to uncover the key biological processes involved in TMP's effects on BCSCs. Further experiments, encompassing micro scale thermophoresis (MST), drug affinity responsive target stability (DARTS), cellular thermal shift assay (CETSA) and amino acid mutation analyses, were utilized to identify the essential targets and corresponding binding sites of TMP. Finally, the effects of TMP on BCSC-like phenotypes were confirmed using cells with mutated amino acid residues, which allowed us to investigate the specificity of TMP's binding sites. To further evaluate the impact of TMP on drug resistance, doxorubicin-resistant MCF7 (MCF-7 ADR ) cells, along with corresponding cell lines harboring mutated amino acid residues, were employed. Results TMP was found to inhibit BCSC-like properties both in vitro and in vivo , evidenced by a reduction in the CD44 + /CD24 - population, sphere formation capability, and expression of stemness markers. Mechanistic studies revealed that TMP targets 3‑hydroxy-3-methylglutaryl-CoA reductase (HMGCR), a rate-limiting enzyme in cholesterol biosynthesis. TMP binds to Asp-767 of HMGCR, thereby inhibiting its activity and reducing cholesterol synthesis. The influence of TMP on BCSC-like phenotypes was nullified by overexpression of wild-type HMGCR, while mutations in the binding site of HMGCR had no effect on TMP's inhibition of BCSC-like properties. Additionally, TMP mitigated MDR by targeting HMGCR. Conclusion These findings suggest that TMP alleviates MDR by reducing BCSC-like traits through targeting HMGCR and disruption of cholesterol biosynthesis in BC. This provides new insights into the mechanisms through which TMP alleviates MDR and offers new lead compound for exploring HMCGR antagonists.
研究领域:
肿瘤学
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药理学
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分子生物学
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细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Theranostics
·
2019
·
IF 8.063
Hui Yu,Jia-Mi Li,Kai Deng,Wei Zhou,Cai-Xia Wang,Qian Wang,Kun-Heng Li,Hong-Yang Zhao,Shi-Wen Huang
The drug resistance in cancer treatment with DOX is mainly related to the overexpression of drug efflux proteins, residing in the plasma and nuclear membranes. Delivering DOX into the mitochondria, lacking drug efflux proteins, is an interesting method to overcome DOX resistance. To solve the problem of positively charged triphenylphosphonium (TPP) for mitochondrial targeting in vivo , a charge reversal strategy was developed. Methods: An acidity triggered cleavable polyanion PEI-DMMA (PD) was coated on the surface of positively charged lipid-polymer hybrid nanoparticle (DOX-PLGA/CPT) to form DOX-PLGA/CPT/PD via electrostatic interaction. The mitochondrial localization and anticancer efficacy of DOX-PLGA/CPT/PD was evaluated both in vitro and in vivo . Results: The surface negative charge of DOX-PLGA/CPT/PD prevents from rapid clearance in the blood and improved the accumulation in tumor tissue through the enhanced permeability and retention (EPR) effect. The hydrolysis of amide bonds in PD in weakly acidic tumor tissue leads to the conversion of DOX-PLGA/CPT/PD to DOX-PLGA/CPT. The positive charge of DOX-PLGA/CPT enhances the interaction with tumor cells, promotes the uptake and improves DOX contents in tumor cells. Once endocytosed by tumor cells, the exposed TPP in nanomedicine results in effective mitochondrial localization of DOX-PLGA/CPT. Afterward, DOX can release from the nanomedicine in the mitochondria, target mtDNA, induce tumor cells apoptosis and overcome DOX resistance of MCF-7/ADR breast cancer. Conclusion: Tumor acidity triggered charge reversal of TPP-containing nanomedicine and activation of mitochondrial targeting is a simple and effective strategy for the delivery of DOX into the mitochondria of cancer cells and overcoming DOX resistance of MCF-7/ADR tumor both in vitro and in vivo , providing new insight in the design of nanomedicines for cancer chemotherapy.
研究领域:
药剂学
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纳米技术
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肿瘤学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Bioengineered
·
2021
·
IF 3.269
Yan Wang,Zhiqiang Cheng,Jing Xu,Meina Lai,Liming Liu,Min Zuo,Lin Dang
Excessive activation of signal transducer and activator of transcription 3 (STAT3) is implicated in breast cancer (BC) chemoresistance, but its underlying mechanism is not fully understood. There are STAT3 binding sites in fat mass and obesity-associated protein (FTO) promoter region, thus STAT3 may regulate the transcription of FTO. This study aimed to investigate the correlation between FTO and STAT3 in BC chemoresistance. Herein, FTO and STAT3 were highly expressed in doxorubicin-resistant BC (BC-DoxR) cells. CHIP assay verified the binding between STAT3 and FTO promoter in BC-DoxR cells. Dual luciferase reporter assay showed that FTO promoter activity was inhibited by S3I-201 (STAT3 inhibitor) but enhanced by epidermal growth factor (EGF, STAT3 activator) in BC-DoxR and BC cells. FTO mRNA and protein expression were suppressed by S3I-201 in BC-DoxR cells and EGF-stimulated BC cells. Notably, FTO regulated total N6-methyladenosine (m6A) levels in BC-DoxR and BC cells but could not affect STAT3 mRNA expression, indicating that FTO was not involved in the m6A modification of STAT3. However, FTO could activate STAT3 signaling in BC-DoxR and BC cells. Besides, FTO knockdown inhibited the doxorubicin resistance of BC-DoxR cells, while FTO overexpression enhanced the doxorubicin resistance and weakened the doxorubicin sensitivity of BC cells. Moreover, decreased doxorubicin resistance by STAT3 knockdown was abolished by FTO overexpression and decreased doxorubicin sensitivity by STAT3 overexpression was reversed by FTO knockdown, indicating that FTO was implicated in STAT3-mediated doxorubicin resistance and impairment of doxorubicin sensitivity of BC cells. Altogether, our findings provide a mechanism underlying BC doxorubicin resistance.
研究领域:
肿瘤学
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分子生物学
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癌症生物学
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药理学
✓ 已验证
DOI
PubMed
高影响因子
CHINESE JOURNAL OF POLYMER SCIENCE
·
2022
·Vol. 41
·期 4
·525-537
·
IF 3.815
Zhou Meng-Xue,Zhang Jia-Yu,Cai Xiao-Meng,Dou Rui,Ruan Li-Fo,Yang Wen-Jiang,Lin Wen-Chu,Chen Jun,Hu Yi
As one of the major challenges in tumor chemotherapy, multidrug resistance typically correlates with the poor drug penetration within tumor tissues and drug efflux by the ATP-driven efflux pumps in tumor cells. Herein, we design a kind of near-infrared (NIR) light- and acidity-activated micellar iPUTDN nanoparticle for mitochondria-targeting doxorubicin (DOX) delivery to combat DOX resistance in small-cell lung cancer. While the PEGylated iPUTDN nanoparticles can keep stealth in blood circulation, NIR irradiation at the tumor region can peel off the PEG shell from the nanoparticles, and the exposed iRGD can facilitate deep tumor penetration of the nanoparticles. After being internalized by DOX-resistant H69AR cells, the poly(β-aminoester)s (PAE)-based nanoparticles can release the triphenylphosphonium (TPP)-conjugated DOX (TDOX) into the cytosol, which can further accumulate in mitochondria with the aid of TPP. Consequently, the mitochondrial membrane potential and ATP content are both reduced in DOX-resistant H69AR cells. The in vivo therapeutic results show that TDOX-loaded nanoparticles with the aid of NIR light irradiation can effectively suppress the DOX-resistant small-cell lung cancer without noticeable adverse effects.
研究领域:
肿瘤学
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药学
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纳米技术
·
癌症研究
✓ 已验证
产品关联
DOI
高影响因子
危险品化学品经营许可证（带存储）