Sulforaphane metabolites reduce resistance to paclitaxel via microtubule disruption

Wang, Yalin; Zhou, Yan; Zheng, Zhongnan; Li, Juntao; Yan, Yu-Ting; Wu, Wei

doi:10.1038/s41419-018-1174-9

Cited by 38 publications

(30 citation statements)

References 50 publications

(80 reference statements)

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“…The dynamics of the microtubules are associated with the grading of malignancy and prognosis of cancer tissues [28]. In our previous research on drug resistance of lung adenocarcinoma, we have found that microtubules can be a target for sulforaphane (SFN) to reduce the drug resistance of paclitaxel (PTX), which agrees well with the above analysis [29].…”

Section: Functional Enrichment Analysis Of Key Genessupporting

confidence: 82%

mRNAsi Index: Machine Learning in Mining Lung Adenocarcinoma Stem Cell Biomarkers

Zhang

Tseng

Lien

et al. 2020

Genes

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Cancer stem cells (CSCs), characterized by self-renewal and unlimited proliferation, lead to therapeutic resistance in lung cancer. In this study, we aimed to investigate the expressions of stem cell-related genes in lung adenocarcinoma (LUAD). The stemness index based on mRNA expression (mRNAsi) was utilized to analyze LUAD cases in the Cancer Genome Atlas (TCGA). First, mRNAsi was analyzed with differential expressions, survival analysis, clinical stages, and gender in LUADs. Then, the weighted gene co-expression network analysis was performed to discover modules of stemness and key genes. The interplay among the key genes was explored at the transcription and protein levels. The enrichment analysis was performed to annotate the function and pathways of the key genes. The expression levels of key genes were validated in a pan-cancer scale. The pathological stage associated gene expression level and survival probability were also validated. The Gene Expression Omnibus (GEO) database was additionally used for validation. The mRNAsi was significantly upregulated in cancer cases. In general, the mRNAsi score increases according to clinical stages and differs in gender significantly. Lower mRNAsi groups had a better overall survival in major LUADs, within five years. The distinguished modules and key genes were selected according to the correlations to the mRNAsi. Thirteen key genes (CCNB1, BUB1, BUB1B, CDC20, PLK1, TTK, CDC45, ESPL1, CCNA2, MCM6, ORC1, MCM2, and CHEK1) were enriched from the cell cycle Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, relating to cell proliferation Gene Ontology (GO) terms, as well. Eight of the thirteen genes have been reported to be associated with the CSC characteristics. However, all of them have been previously ignored in LUADs. Their expression increased according to the pathological stages of LUAD, and these genes were clearly upregulated in pan-cancers. In the GEO database, only the tumor necrosis factor receptor associated factor-interacting protein (TRAIP) from the blue module was matched with the stemness microarray data. These key genes were found to have strong correlations as a whole, and could be used as therapeutic targets in the treatment of LUAD, by inhibiting the stemness features.

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Section: Functional Enrichment Analysis Of Key Genessupporting

confidence: 82%

mRNAsi Index: Machine Learning in Mining Lung Adenocarcinoma Stem Cell Biomarkers

Zhang

Tseng

Lien

et al. 2020

Genes

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“…BCl-2 expression regulation by microtubule acetylation inhibitors should be explored in subsequent studies; nevertheless, it is expected that there would be no resistance problem with the effective inhibition of BCl-2 expression. Moreover, microtubule disruption is known to effectively reduce anticancer drug resistance caused by the long-term administration of Taxol [ 57 ]. In this study, treatment with microtubule acetylation inhibitors showed that microtubule bundles were disrupted in acetylation-enriched cells; thus, they could be used in combination therapy under the appropriate conditions.…”

Section: Discussionmentioning

confidence: 99%

Potent Small-Molecule Inhibitors Targeting Acetylated Microtubules as Anticancer Agents Against Triple-Negative Breast Cancer

et al. 2020

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Microtubules are one of the major targets for anticancer drugs because of their role in cell proliferation and migration. However, as anticancer drugs targeting microtubules have side effects, including the death of normal cells, it is necessary to develop anticancer agents that can target microtubules by specifically acting on cancer cells only. In this study, we identified chemicals that can act as anticancer agents by specifically binding to acetylated microtubules, which are predominant in triple-negative breast cancer (TNBC). The chemical compounds disrupted acetylated microtubule lattices by interfering with microtubule access to alpha-tubulin acetyltransferase 1 (αTAT1), a major acetyltransferase of microtubules, resulting in the increased apoptotic cell death of MDA-MB-231 cells (a TNBC cell line) compared with other cells, such as MCF-10A and MCF-7, which lack microtubule acetylation. Moreover, mouse xenograft experiments showed that treatment with the chemical compounds markedly reduced tumor growth progression. Taken together, the newly identified chemical compounds can be selective for acetylated microtubules and act as potential therapeutic agents against microtubule acetylation enrichment in TNBC.

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“…On the other hand, acquired resistance may develop over time after the chemotherapeutic exposure [107]. Accordingly, treatment with PTX might increase acquired resistance, which leads to chemotherapy failure [108]. Importantly, the mechanisms associated with the challenging and complex nature of chemoresistance [107] are still not clear [109].…”

Section: Breast Tumor Resistance To Paclitaxelmentioning

confidence: 99%

Paclitaxel’s Mechanistic and Clinical Effects on Breast Cancer

et al. 2019

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Paclitaxel (PTX), the most widely used anticancer drug, is applied for the treatment of various types of malignant diseases. Mechanisms of PTX action represent several ways in which PTX affects cellular processes resulting in programmed cell death. PTX is frequently used as the first-line treatment drug in breast cancer (BC). Unfortunately, the resistance of BC to PTX treatment is a great obstacle in clinical applications and one of the major causes of death associated with treatment failure. Factors contributing to PTX resistance, such as ABC transporters, microRNAs (miRNAs), or mutations in certain genes, along with side effects of PTX including peripheral neuropathy or hypersensitivity associated with the vehicle used to overcome its poor solubility, are responsible for intensive research concerning the use of PTX in preclinical and clinical studies. Novelties such as albumin-bound PTX (nab-PTX) demonstrate a progressive approach leading to higher efficiency and decreased risk of side effects after drug administration. Moreover, PTX nanoparticles for targeted treatment of BC promise a stable and efficient therapeutic intervention. Here, we summarize current research focused on PTX, its evaluations in preclinical research and application clinical practice as well as the perspective of the drug for future implication in BC therapy.

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Sulforaphane metabolites reduce resistance to paclitaxel via microtubule disruption

Cited by 38 publications

References 50 publications

mRNAsi Index: Machine Learning in Mining Lung Adenocarcinoma Stem Cell Biomarkers

mRNAsi Index: Machine Learning in Mining Lung Adenocarcinoma Stem Cell Biomarkers

Potent Small-Molecule Inhibitors Targeting Acetylated Microtubules as Anticancer Agents Against Triple-Negative Breast Cancer

Paclitaxel’s Mechanistic and Clinical Effects on Breast Cancer

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