Targeting signal transduction pathways to eliminate chemotherapeutic drug resistance and cancer stem cells

The overall five-year survival rate for late-stage patients of ovarian cancer is below 29% due to disease recurrence and drug resistance. Cancer stem cells (CSCs) are known as a major contributor to drug resistance and recurrence. Accordingly, therapies targeting ovarian CSCs are needed to overcome the limitations of present treatments. This study evaluated the effect of trimebutine maleate (TM) targeting ovarian CSCs, using A2780-SP cells acquired by a sphere culture of A2780 epithelial ovarian cancer cells. TM is indicated as a gastrointestinal motility modulator and is known to as a peripheral opioid receptor agonist and a blocker for various channels. The GI50 of TM was approximately 0.4 µM in A2780-SP cells but over 100 µM in A2780 cells, demonstrating CSCs specific growth inhibition. TM induced G0/G1 arrest and increased the AV+/PI+ dead cell population in the A2780-SP samples. Furthermore, TM treatment significantly reduced tumor growth in A2780-SP xenograft mice. Voltage gated calcium channels (VGCC) and calcium-activated potassium channels (BKCa) were overexpressed on ovarian CSCs and targeted by TM; inhibition of both channels reduced A2780-SP cells viability. TM reduced stemness-related protein expression; this tendency was reproduced by the simultaneous inhibition of VGCC and BKCa compared to single channel inhibition. In addition, TM suppressed the Wnt/β-catenin, Notch, and Hedgehog pathways which contribute to many CSCs characteristics. Specifically, further suppression of the Wnt/β-catenin pathway by simultaneous inhibition of BKCa and VGCC is necessary for the effective and selective action of TM. Taken together, TM is a potential therapeutic drug for preventing ovarian cancer recurrence and drug resistance.

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The impact of fusion genes on cancer stem cells and drug resistance

Molecular and Cellular Biochemistry ◽

10.1007/s11010-021-04203-4 ◽

2021 ◽

Author(s):

Saurav Panicker ◽

Sivaramakrishnan Venkatabalasubramanian ◽

Surajit Pathak ◽

Satish Ramalingam

Keyword(s):

Stem Cells ◽

Drug Resistance ◽

Cancer Stem Cells ◽

Fusion Genes ◽

The Impact

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Shooting the messenger: Targeting signal transduction pathways in leukemia and related disorders

Critical Reviews in Oncology/Hematology ◽

10.1016/j.critrevonc.2010.05.002 ◽

2011 ◽

Vol 78 (1) ◽

pp. 33-44 ◽

Cited By ~ 7

Author(s):

Suzita M. Noor ◽

Richard Bell ◽

Alister C. Ward

Keyword(s):

Signal Transduction ◽

Signal Transduction Pathways ◽

Targeting Signal

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Natural products targeting cancer stem cells: a revisit

Current Medicinal Chemistry ◽

10.2174/0929867328666210405111913 ◽

2021 ◽

Vol 28 ◽

Author(s):

Jiahua Cui ◽

Jiajun Qian ◽

Larry Ming-Cheung Chow ◽

Jinping Jia

Keyword(s):

Stem Cells ◽

Drug Resistance ◽

Natural Products ◽

Cancer Stem Cells ◽

Therapeutic Potential ◽

Tumor Development ◽

Biologically Active ◽

Cellular Targets ◽

Drug Candidates ◽

Enhanced Expression

Background: The proposed central role of cancer stem cells (CSCs) in tumor development has been extended to explain the diverse oncologic phenomena such as multidrug resistance, metastasis and tumor recurrence in clinics. Due to the enhanced expression of ATP-binding cassette transporters and anti-apoptotic factors, stagnation on G0 phase and the strong ability of self-renewal, the CSCs were highly resistant to clinical anticancer drugs. Therefore, the discovery of new drug candidates that could effectively eradicate cancer stem cells afforded promising outcomes in cancer therapy. Introduction: Natural products and their synthetic analogues are a rich source of biologically active compounds and several of them have already been recognized as potent CSCs killers. We aim to provide a collection of recently identified natural products that suppressed the survival of the small invasive CSC populations and combated the drug resistance of these cells in chemotherapy. Results and Conclusion: These anti-CSCs natural products included flavonoids, stilbenes, quinones, terpenoids, polyketide antibiotics, steroids and alkaloids. In the present review, we highlighted the therapeutic potential of natural products and their derivatives against the proliferation and drug resistance of CSCs, their working mechanisms and related structure-activity relationships. Meanwhile, in this survey, several natural products with diverse cellular targets such as the naphthoquinone shikonin and the stilbene resveratrol were characterized as promising lead compounds for future development.

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Targeting signal transduction pathways in melanoma

Melanoma Research ◽

10.1097/01.cmr.0000382784.44182.71 ◽

2010 ◽

Vol 20 ◽

pp. e20

Author(s):

K.T. Flaherty

Keyword(s):

Signal Transduction ◽

Signal Transduction Pathways ◽

Targeting Signal

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MicroRNA Targeted Therapy for Overcoming Drug Resistance, Reversal of EMT and Elimination of Cancer Stem Cells in Prostate and Pancreatic Cancer

MicroRNA Targeted Cancer Therapy ◽

10.1007/978-3-319-05134-5_12 ◽

2014 ◽

pp. 199-217 ◽

Cited By ~ 3

Author(s):

Yiwei Li ◽

Dejuan Kong ◽

Aamir Ahmad ◽

Bin Bao ◽

Fazlul H. Sarkar

Keyword(s):

Pancreatic Cancer ◽

Stem Cells ◽

Drug Resistance ◽

Targeted Therapy ◽

Cancer Stem Cells ◽

Resistance Reversal

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Long noncoding RNA LINC00261 upregulates ITIH5 to impair tumorigenic ability of pancreatic cancer stem cells

Cell Death Discovery ◽

10.1038/s41420-021-00575-0 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Lijuan Zou ◽

Hengpeng He ◽

Zhiguo Li ◽

Ou Chen ◽

Xiukun Jia ◽

...

Keyword(s):

Pancreatic Cancer ◽

Stem Cells ◽

Cell Proliferation ◽

Drug Resistance ◽

Cancer Stem Cells ◽

Noncoding Rna ◽

Cell Subset ◽

Luciferase Reporter ◽

Stem Cell Markers ◽

Self Renewal

AbstractLong noncoding RNAs (lncRNAs) are implicated tumor development in a range of different cancers, including pancreatic cancer (PC). Cancer stem cells (CSCs), a drug-resistant cancer cell subset, drive tumor progression in PC. In this work, we aimed to investigate the mechanism by which lncRNA LINC00261 affects the biological functions of CSCs during the progression of PC. Microarray analysis of differentially expressed genes and lncRNAs suggested that LINC00261 is downregulated in PC. Both LINC00261 and ITIH5 were confirmed to be downregulated in PC cells and PC stem cells. Gain-of-function and loss-of-function investigations were performed to analyze their effects on cell proliferation, drug resistance, cell cycle distribution, self-renewal, invasion, and ultimately overall tumorigenicity. These experiments revealed that the expression of stem cell markers was reduced, and cell proliferation, self-renewal ability, cell invasion, drug resistance, and tumorigenicity were all suppressed by upregulation of LINC00261 or ITIH5. The results of dual-luciferase reporter gene, ChIP, and RIP assays indicated that LINC00261 binds directly to GATA6, increasing its activity at the ITIH5 promoter. The presence of LINC00261 and GATA6 inhibited the self-renewal and tumorigenesis of PC stem cells, while silence of ITIH5 rescued those functions. Collectively, this study identifies the tumor suppressive activity of LINC00261 in PC, showing that this lncRNA limits the functions of PC stem through an ITIH5/GATA6 regulatory pathway.

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