scholarly journals Deubiquitinating Enzyme Inhibitor Alleviates Cyclin A1-mediated Proteasome Inhibitor Tolerance in Mixed-lineage Leukemia

2020 ◽  
Author(s):  
Maolin Ge ◽  
Qiongyu Xu ◽  
Ting Kang ◽  
Dan Li ◽  
Ruiheng Wang ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Drug Resistance ◽  
Cancer Cells ◽  
Proteasome Inhibitor ◽  
Enzyme Inhibitor ◽  
Mixed Lineage Leukemia ◽  
Deubiquitinating Enzyme ◽  
Protein Loss ◽  
Cyclin A1 ◽  
Inhibitor Tolerance

Abstract Background: Drug resistance is a significant obstacle to effective cancer treatment. Drug resistance develops from initially reversible drug-tolerant cancer cells, which offers therapeutic opportunities to impede cancer relapse. The mechanisms of resistance to proteasome inhibitor (PI) therapy have been investigated intensively; however, the ways by which drug-tolerant cancer cells orchestrate their adaptive responses to drug challenges remains largely unknown. Methods: RNA sequencing and bioinformatics analyses were employed to assess dysregulated cell cycle genes. Chromatin immunoprecipitation assays were performed to evaluate the involvement of MLL in cyclin A1 transcriptional activity. Cell cycle assays, cell viability assays, immunoblots, and apoptosis assays were performed to evaluate the dependency of cyclin A1 during tolerance acquisition.Results: Here, we demonstrated that cyclin A1 suppression elicited the development of transient PI tolerance in mixed-lineage leukemia (MLL) cells. This adaptive process involved reversible down-regulation of cyclin A1, which promoted PI resistance through cell cycle arrest. PI-tolerant MLL cells acquired cyclin A1 dependency, regulated directly by MLL protein. Loss of cyclin A1 function resulted in the emergence of drug tolerance, which was associated with patient relapse and reduced survival. Combination treatment with PI and deubiquitinating enzyme (DUB) inhibitors overcame this drug resistance by restoring cyclin A1 expression through chromatin crosstalk between histone H2B monoubiquitination and MLL-mediated histone H3 lysine 4 methylation. Conclusion: These results reveal the importance of cyclin A1-engaged cell cycle regulation in PI resistance in MLL cells, and suggest that cell cycle re-entry by DUB inhibitors may represent a promising epigenetic therapeutic strategy to prevent acquired drug resistance.

MG132 as a proteasome inhibitor induces cell growth inhibition and cell death in A549 lung cancer cells via influencing reactive oxygen species and GSH level

2010 ◽  
Vol 29 (7) ◽  
pp. 607-614 ◽  
Author(s):  
Yong Hwan Han ◽  
Woo Hyun Park
Keyword(s):  
Lung Cancer ◽  
Reactive Oxygen Species ◽  
Cell Cycle ◽  
Cell Death ◽  
Cancer Cells ◽  
Proteasome Inhibitor ◽  
A549 Cells ◽  
Lung Cancer Cells ◽  
Oxygen Species ◽  
A549 Lung

Carbobenzoxy-Leu-Leu-leucinal (MG132) as a proteasome inhibitor has been shown to induce apoptotic cell death through formation of reactive oxygen species (ROS). In the present study, we evaluated the effects of MG132 on the growth of A549 lung cancer cells in relation to cell growth, ROS and glutathione (GSH) levels. Treatment with MG132 inhibited the growth of A549 cells with an IC50 of approximately 20 μM at 24 hours. DNA flow cytometric analysis indicated that 0.5 ∼ 30 μM MG132 induced a G1 phase arrest of the cell cycle in A549 cells. Treatment with 10 or 30 μM MG132 also induced apoptosis, as evidenced by sub-G1 cells and annexin V staining cells. This was accompanied by the loss of mitochondrial membrane potential (MMP; Δψm). The intracellular ROS levels including O2•- were strongly increased in 10 or 30 μM MG132-treated A549 cells but were down-regulated in 0.1, 0.5 or 1 μM MG132-treated cells. Furthermore, 10 or 30 μM MG132 increased mitochondrial O2•- level but 0.1, 0.5 or 1 μM MG132 decreased that. In addition, 10 or 30 μM MG132 induced GSH depletion in A549 cells. In conclusion, MG132 inhibited the growth of human A549 cells via inducing the cell cycle arrest as well as triggering apoptosis, which was in part correlated with the changes of ROS and GSH levels. Our present data provide important information on the anti-growth mechanisms of MG132 in A549 lung cancer cells in relation to ROS and GSH.

scholarly journals Research of the mechanism on miRNA193 in exosomes promotes cisplatin resistance in esophageal cancer cells

2019 ◽  
Author(s):  
Shifeng Shi ◽  
Xin Huang ◽  
Xiao Ma ◽  
Xiaoyan Zhu ◽  
Qinxian Zhang
Keyword(s):  
Cell Cycle ◽  
Drug Resistance ◽  
Esophageal Cancer ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Cisplatin Resistance ◽  
High Expression ◽  
Drug Resistant ◽  
Cellular Resistance ◽  
Esophageal Cancer Cells

AbstractPurposeChemotherapy resistance of esophageal cancer is a key factor affecting the postoperative treatment of esophageal cancer. Among the media that transmit signals between cells, the exosomes secreted by tumor cells mediate information transmission between tumor cells, which can make sensitive cells obtain resistance. Although some cellular exosomes play an important role in tumor’s acquired drug resistance, the related action mechanism is still not explored specifically.MethodsTo elucidate this process, we constructed a cisplatin-resistant esophageal cancer cell line, and proved that exosomes conferring cellular resistance in esophageal cancer can promote cisplatin resistance in sensitive cells. Through high-throughput sequencing analysis of the exosome and of cells after stimulation by exosomes, we determined that the miRNA193 in exosomes conferring cellular resistance played a key role in sensitive cells acquiring resistance to cisplatin. In vitro experiments showed that miRNA193 can regulate the cell cycle of esophageal cancer cells and inhibit apoptosis, so that sensitive cells can acquire resistance to cisplatin. An in vivo experiment proved that miRNA193 can promote tumor proliferation through the exosomes, and provide sensitive cells with slight resistance to cisplatin.ResultsSmall RNA sequencing of exosomes showed that exosomes in drug-resistant cells have 189 up-regulated and 304 down-regulated miRNAs; transcriptome results showed that drug-resistant cells treated with drug-resistant cellular exosomes have 3446 high-expression and 1709 low-expression genes; correlation analysis showed that drug-resistant cellular exosomes mainly affect the drug resistance of sensitive cells through paths such as cytokine–cytokine receptor interaction, and the VEGF and Jak-STAT signaling pathways; miRNA193, one of the high-expression miRNAs in drug-resistant cellular exosomes, can promote drug resistance by removing cisplatin’s inhibition of the cell cycle of sensitive cells.ConclusionSensitive cells can become resistant to cisplatin through acquired drug-resistant cellular exosomes, and miRNA193 can make tumor cells acquire cisplatin resistance by regulating the cell cycle.

scholarly journals Exosomes derived from cancer stem cells of gemcitabine-resistant pancreatic cancer cells enhance drug resistance by delivering miR-210

2019 ◽  
Vol 43 (1) ◽  
pp. 123-136 ◽  
Author(s):  
Zhiyong Yang ◽  
Ning Zhao ◽  
Jing Cui ◽  
Heshui Wu ◽  
Jiongxin Xiong ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Pancreatic Cancer ◽  
Stem Cells ◽  
Drug Resistance ◽  
Cancer Stem Cells ◽  
Cancer Cells ◽  
Dependent Manner ◽  
Expression Levels ◽  
Pancreatic Cancer Cells ◽  
Pancreatic Cancer Stem Cells

Abstract Purpose Gemcitabine (GEM)-based chemotherapy is the first-line treatment for locally advanced pancreatic cancer. GEM resistance, however, remains a significant clinical challenge. Here, we investigated whether exosomes derived from GEM-resistant pancreatic cancer stem cells (CSCs) mediate cell-cell communication between cells that are sensitive or resistant to GEM and, by doing so, regulate drug resistance. Methods GEM-sensitive BxPC-3-derived BxS and PANC-1 pancreatic cancer cells were cultured with exosomes extracted from CSCs isolated from GEM-resistant BxPC-3-derived BxR cells (BxR-CSC). The effect of exosomes on drug resistance, cell cycle progression, apoptosis and miRNA expression was evaluated in BxS and PANC-1 cells. Relevant miRNAs associated with GEM resistance were identified and the role of miR-210 in conferring drug resistance was examined in vitro and in vivo. Results BxR-CSC-derived exosomes induced GEM resistance, inhibited GEM-induced cell cycle arrest, antagonized GEM-induced apoptosis, and promoted tube formation and cell migration in BxS and PANC-1 cells. Elevated miR-210 expression levels were detected in BxR-CSCs and BxR-CSC-derived exosomes compared to those in BxS-CSCs and BxS-CSC-derived exosomes. In addition, increased expression levels of miR-210 were observed in BxS and PANC-1 cells cultured with BxR-CSC-derived exosomes upon exposure to GEM in a dose-dependent manner. Also, a series of biological changes was observed in BxS cells after transfection with miR-210 mimics, including activation of the mammalian target of rapamycin (mTOR) signaling pathway, and these changes were similar to those triggered by BxR-CSC-derived exosomes. Conclusions Our findings suggest that exosomes derived from GEM-resistant pancreatic cancer stem cells mediate the horizontal transfer of drug-resistant traits to GEM-sensitive pancreatic cancer cells by delivering miR-210.

scholarly journals A Comparative Study of the Anticancer Activity and PARP-1 Inhibiting Effect of Benzofuran–Pyrazole Scaffold and Its Nano-Sized Particles in Human Breast Cancer Cells

Molecules ◽  
2019 ◽  
Vol 24 (13) ◽  
pp. 2413 ◽  
Author(s):  
Manal M. Anwar ◽  
Somaia S. Abd El-Karim ◽  
Ahlam H. Mahmoud ◽  
Abd El-Galil E. Amr ◽  
Mohamed A. Al-Omar
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Cancer Cells ◽  
Human Breast Cancer ◽  
Breast Cancer Cells ◽  
Caspase 3 ◽  
Enzyme Inhibitor ◽  
Human Breast Cancer Cells ◽  
Human Breast ◽  
Parp 1

Breast cancer is considered the most common and deadly cancer among women worldwide. Nanomedicine has become extremely attractive in the field of cancer treatment. Due to the high surface to volume ratio and other unique properties, nanomaterials can be specifically targeted to certain cells and tissues to interact with the living systems. The strategic planning of this study is based on using the nanoprecipitation method to prepare nanoparticles BZP-NPs (3.8–5.7 nm) of the previously prepared benzofuran–pyrazole compound (IV) BZP which showed promising cytotoxic activity. The capacity of BZP and BZP-NPs to suppress the growth of human breast tumor MCF-7 and MDA-MB-231 cells was evaluated using MTT assay. The IC50 doses of BZP and BZP-NPs targeting normal breast cells MCF-12A exceeded those targeting the cancer cells by >1000-fold, demonstrating their reasonable safety profiles in normal cells. Furthermore, cell cycle analysis, apoptosis induction detection, assessment of p53, Bcl-2, caspase-3, and PARP-1 levels of BZP and its nano-sized-BZP-NPs particles were also evaluated. Although the obtained results were in the favor of compound IV in its normal-sized particles, BZP-NPs appeared as a hit compound which showed improved cytotoxicity against the tested human breast cancer cells associated with the induction of pre-G1 apoptosis as well as cell cycle arrest at G2/M phase. The increase in caspase-3 level, upregulation of p53, and downregulation of Bcl-2 protein expression levels confirmed apoptosis. Furthermore, ELISA results exhibited that BZP-NPs produced a more favorable impact as a PARP-1 enzyme inhibitor than the parent BZP.

scholarly journals Inhibition of Tyrosine 3-Monooxygenase/Tryptophan 5-Monooxygenase Activation Protein Zeta (YWHAZ) Overcomes Drug Resistance and Tumorigenicity in Ovarian Cancer

2018 ◽  
Vol 49 (1) ◽  
pp. 53-64 ◽  
Author(s):  
Lan Hong ◽  
Wangsheng  Chen ◽  
Aiwen Xing ◽  
Dongcai Wu ◽  
Shengtan Wang
Keyword(s):  
Cell Cycle ◽  
Ovarian Cancer ◽  
Drug Resistance ◽  
Stem Cell ◽  
Cancer Cells ◽  
Functional Role ◽  
Ovarian Cancer Cells ◽  
Stem Cell Markers ◽  
Western Blots

Background/Aims: Cancer stem-like cells are the main cause of tumor occurrence, progression, and therapeutic resistance. However, the precise signals required for the maintenance of the stem-like traits of these cells in ovarian cancer remain elusive. We have thus worked to elucidate the functional role of Tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein zeta (YWHAZ), a gene encoding the 14-3-3ζ protein, in the regulation of multidrug resistance and stem cell-like traits in ovarian cancer. Methods: We detected the YWHAZ levels in human ovarian cancer specimens and cell lines using quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and western blots. MTS assays, soft agar colony formation assays, migration assays, cell cycle analysis, sphere formation assays, and flow cytometry were applied to investigate the functional role of YWHAZ in ovarian cancer. Results: Our data reveals substantially increased YWHAZ expression in both cisplatin- and paclitaxel-resistant ovarian cancer cells. Silencing YWHAZ restored the sensitivity of resistant ovarian cancer cells to cisplatin and paclitaxel. Furthermore, in vitro studies showed that down-regulation of YWHAZ inhibited cell cycle progression, migration, and the expression of stem cell markers. Moreover, tumorigenicity was suppressed in tumor-bearing BALB/c nude mice following YWHAZ knockdown. Additionally, we demonstrated that the expression of YWHAZ was directly down-regulated by miR-30e in resistant ovarian cancer cells. Conclusion: Our results have led to new insights into the essential role of YWHAZ in the regulation of tumourigenesis, stem-like traits, and drug resistance in ovarian cancer, thereby helping to identify a potential target for ovarian cancer therapy.

scholarly journals Plumbagin Induces Cell Cycle Arrest and Apoptosis in A431 Cisplatin-Resistant Cancer Cells

2020 ◽  
Vol 15 (4) ◽  
pp. 1934578X2092162
Author(s):  
Isabella Giacomini ◽  
Veronica Cocetta ◽  
Maria Carrara ◽  
Eugenio Ragazzi ◽  
Monica Montopoli
Keyword(s):  
Cell Cycle ◽  
Drug Resistance ◽  
Cell Cycle Arrest ◽  
Cancer Cells ◽  
Cell Line ◽  
Cancer Cell Line ◽  
Squamous Carcinoma ◽  
Resistant Cell Line ◽  
Cycle Arrest

The onset of drug resistance represents the leading cause of chemotherapy failure in clinics. In the last decades, natural compounds have emerged as possible anticancer strategies used either alone or in combination with chemotherapeutic drugs, in order to overcome drug resistance. In fact, plant-derived therapies present biological activity and minimal side effects showing promising roles in the resensitization of resistant cancer cells. This work was aimed at investigating the anticancer potential of the natural naphthoquinone plumbagin in a cisplatin-resistant cancer cell line. The results indicated cytotoxic and pro-oxidant activity of plumbagin in both sensitive (A431wt) and cisplatin-resistant (A431/Pt) human cervix squamous carcinoma cell lines. Moreover, plumbagin treatment induced cell cycle arrest and apoptosis in A431/Pt cells and the inhibition of retinoblastoma complex, suggesting a stronger activity on the cisplatin-resistant cell line. Taken together, the data indicate appreciable in vitro anticancer activity of plumbagin, suggesting that this natural compound could become a tool to overcome cisplatin resistance. Although further studies are necessary, this work underlines a promising role of plumbagin in the resensitization of cisplatin-resistant cancer cells.

scholarly journals HIV Protease Inhibitor Nelfinavir Targets Human DDI2 and Potentiates Proteasome Inhibitor-based Chemotherapy

2020 ◽  
Author(s):  
Yuan Gu ◽  
Xin Wang ◽  
Yu Wang ◽  
Jie Li ◽  
Fa-Xing Yu
Keyword(s):  
Drug Resistance ◽  
Protease Inhibitor ◽  
Cancer Cells ◽  
Proteasome Inhibitor ◽  
Clinical Evidence ◽  
Proteasome Inhibitors ◽  
Hiv Protease ◽  
Compensatory Mechanism ◽  
Nuclear Factor ◽  
Hiv Protease Inhibitor

AbstractProteasome inhibitors (PIs) are currently used in the clinic to treat cancers such as multiple myeloma (MM). However, cancer cells often rapidly develop drug resistance towards PIs due to a compensatory mechanism mediated by nuclear factor erythroid 2 like 1 (NFE2L1) and aspartic protease DNA damage inducible 1 homolog 2 (DDI2). Following DDI2-mediated cleavage, NFE2L1 is able to induce transcription of virtually all proteasome subunit genes. Under normal condition, cleaved NFE2L1 is constantly degraded by proteasome, whereas in the presence of PIs, it accumulates and induces proteasome synthesis which in turn promotes the development of drug resistance towards PIs. Here, we report that Nelfinavir (NFV), an HIV protease inhibitor, can inhibit DDI2 activity directly. Inhibition of DDI2 by NFV effectively blocks NFE2L1 proteolysis and potentiates cytotoxicity of PIs in cancer cells. Recent clinical evidence indicated that NFV can effectively delay the refractory period of MM patients treated with PI-based therapy. Our finding hence provides a specific molecular mechanism for combinatorial therapy using NFV and PIs for treating MM and probably additional cancers.Abstract Figure

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