The Mechanisms of the Growth Inhibitory Effects of Paclitaxel on Gefitinib-resistant Non-small Cell Lung Cancer Cells

Mohiuddin, Md.; Kondo, Kazuo

doi:10.21873/cgp.20288

Cited by 12 publications

(5 citation statements)

References 67 publications

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“…Recent reports also show that low-concentration PTX can kill cancer cells indirectly through inhibiting the proliferation of human endothelial cells and reducing the expression of angiogenesis markers, such as VEGF, TGFA and FGF, to lessen the input of nutrition [ 8 ]. Apoptosis is also one of the important ways in which PTX exerts its antineoplastic effect, but the signaling pathways involved are distinct in different cancer cells [ 9 , 10 ].…”

Section: Introductionmentioning

confidence: 99%

Paclitaxel Induces the Apoptosis of Prostate Cancer Cells via ROS-Mediated HIF-1α Expression

Zhang

Tang

et al. 2022

Molecules

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Prostate cancer (PCa) is the most common malignancy to endanger the health of male genitourinary system. Clinically, paclitaxel (PTX) (C47H51NO14), a diterpene alkaloid, is commonly used as an effective natural antineoplastic drug during the treatment of PCa. However, the mechanism and pathway involved in the function of PTX are poorly understood. In the current study, we employed the CCK-8 assay, revealing that PTX can inhibit the survival and induce the apoptosis of PC3M cells (a human prostate cancer cell line) in a concentration-dependent manner. Reactive oxygen species (ROS), as a metabolic intermediate produced by the mitochondrial respiratory chain, are highly accumulated under the PTX treatment, which results in a sharp decrease of the mitochondrial membrane potential in PC3M cells. Additionally, the migration and invasion of PC3M cells are weakened due to PTX treatment. Further analysis reveals that N-acetylcysteine (NAC), which functions as an antioxidant, not only rescues the decreased mitochondrial membrane potential induced by the abnormal ROS level, but also restores the migration and invasion of PC3M cells. In a subsequent exploration of the detailed mechanism, we found that hypoxia-inducible factor (HIF)-1α works as a downstream gene that can respond to the increased ROS in PC3M cells. Under PTX treatment, the expression levels of HIF-1α mRNA and protein are significantly increased, which stimulate the activation of JNK/caspase-3 signaling and promote the apoptosis of PC3M cells. In summary, we demonstrate that PTX regulates the expression of HIF-1α through increased ROS accumulation, thereby promoting the activation of JNK/caspase-3 pathway to induce the apoptosis of PCa cells. This study provides new insights into the mechanism of antineoplastic action of taxanes and unveils the clinical benefit of the ROS-HIF-1α signaling pathway, which may offer a potential therapeutic target to prevent the development of PCa.

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Section: Introductionmentioning

confidence: 99%

Paclitaxel Induces the Apoptosis of Prostate Cancer Cells via ROS-Mediated HIF-1α Expression

Zhang

Tang

et al. 2022

Molecules

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“…PTX exerts its cytotoxic effect by arresting mitosis through microtubule stabilization or reactive oxygen species (ROS)‐mediated DNA damage, resulting in cellular apoptosis. [ 26 ] CHEK2 is a core component of the DNA damage response in tumor cells, phosphorylating the downstream kinase CDC25 and preventing damaged cells from mitosis to provide extra time for DNA repair. [ 27 ] Next, We detected the expression of p‐CHEK2/CHEK2 and its downstream targets, including cell cycle related protein CDC25A, CDC25B, and CDC25C.…”

Section: Resultsmentioning

confidence: 99%

Microenvironmentally Responsive Chemotherapeutic Prodrugs and CHEK2 Inhibitors Self‐Assembled Micelles: Protecting Fertility and Enhancing Chemotherapy

Xue

Guo

et al. 2023

Advanced Materials

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Chemotherapy is a widely used and effective adjuvant treatment for cancer, and it has unavoidable damage to female fertility, with statistics showing 38% of women who have received chemotherapy are infertile. How to reduce fertility toxicity while enhancing the oncologic chemotherapy is a clinical challenge. Herein, co‐delivery micelles (BML@PMP) are developed, which are composed of a reduction‐sensitive paclitaxel prodrug (PMP) for chemotherapy and a CHEK2 inhibitor (BML277) for both fertility protection and chemotherapy enhancement. BML@PMP achieves fertility protection through three actions: (1) Due to the enhanced permeability and retention (EPR) effect, BML@PMP is more enriched in the tumor, while very little in the ovary (about 1/10th of the tumor). (2) Glutathione (GSH) triggers the release of PTX, and with low levels of GSH in the ovary, the amount of PTX released in the ovary is correspondingly reduced. (3) BML277 inhibits oocyte apoptosis by inhibiting the CHEK2‐TAp63α pathway. Because of the different downstream targets of CHEK2 in tumor cells and oocytes, BML277 also enhances chemotherapeutic efficacy by reducing DNA damage repair which is activated through the CHEK2 pathway. This bidirectional effect of CHEK2 inhibitor‐based co‐delivery system represents a promising strategy for improving oncology treatment indices and preventing chemotherapy‐associated fertility damage.

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“…Our results are consistent with the results of a previous study that showed that PTX-induced ROS accumulation stimulates the expression of HIF-1α and activates caspase-3 signaling to promote apoptosis in prostate cancer cells [ 27 ]. Notably, PTX can bind to β-tubulin and prevent the dissociation of microtubules, blocking cell cycle progression, and also inducing apoptosis and senescence through the distinct signaling pathways involved in different cancer cells [ 28 , 29 ].…”

Section: Discussionmentioning

confidence: 99%

“…HMGA2 overexpression has been and is associated with poor prognosis, low survival rates, and advanced stage in various types of human cancer. HMGA2 protein is an independent indicator of shorter patient survival time and tumor progression in several cancers, including gastric cancer, oral squamous cell carcinoma, and bladder cancer [ 28 ]. The mouse that had the intestine-specific Hmga2 overexpression accelerated azoxymethane (AOM)/dextran sodium sulfate (DSS) carcinogen-induced tumor development [ 30 ], suggesting an important role of HMGA2 in colorectal cancer development.…”

Section: Discussionmentioning

confidence: 99%

HMGA2 promotes resistance against paclitaxel by targeting the p53 signaling pathway in colorectal cancer cells

Jiang,

Li,

Zhou

et al. 2024

Heliyon

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The Mechanisms of the Growth Inhibitory Effects of Paclitaxel on Gefitinib-resistant Non-small Cell Lung Cancer Cells

Cited by 12 publications

References 67 publications

Paclitaxel Induces the Apoptosis of Prostate Cancer Cells via ROS-Mediated HIF-1α Expression

Paclitaxel Induces the Apoptosis of Prostate Cancer Cells via ROS-Mediated HIF-1α Expression

Microenvironmentally Responsive Chemotherapeutic Prodrugs and CHEK2 Inhibitors Self‐Assembled Micelles: Protecting Fertility and Enhancing Chemotherapy

HMGA2 promotes resistance against paclitaxel by targeting the p53 signaling pathway in colorectal cancer cells

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