The development of drug resistance through reversion mutation in BRCA genes in ovarian cancer

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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SENP1-mediated deSUMOylation of JAK2 regulates its kinase activity and platinum drug resistance

Cell Death and Disease ◽

10.1038/s41419-021-03635-6 ◽

2021 ◽

Vol 12 (4) ◽

Author(s):

Jing Li ◽

Ruiqin Wu ◽

Mingo M. H. Yung ◽

Jing Sun ◽

Zhuqing Li ◽

...

Keyword(s):

Ovarian Cancer ◽

Drug Resistance ◽

Kinase Activity ◽

Regulatory Mechanism ◽

Platinum Resistance ◽

Platinum Drug ◽

Clinical Prognosis ◽

Platinum Resistant ◽

Poor Clinical Prognosis ◽

Stat Pathway

AbstractThe JAK2/STAT pathway is hyperactivated in many cancers, and such hyperactivation is associated with a poor clinical prognosis and drug resistance. The mechanism regulating JAK2 activity is complex. Although translocation of JAK2 between nucleus and cytoplasm is an important regulatory mechanism, how JAK2 translocation is regulated and what is the physiological function of this translocation remain largely unknown. Here, we found that protease SENP1 directly interacts with and deSUMOylates JAK2, and the deSUMOylation of JAK2 leads to its accumulation at cytoplasm, where JAK2 is activated. Significantly, this novel SENP1/JAK2 axis is activated in platinum-resistant ovarian cancer in a manner dependent on a transcription factor RUNX2 and activated RUNX2/SENP1/JAK2 is critical for platinum-resistance in ovarian cancer. To explore the application of anti-SENP1/JAK2 for treatment of platinum-resistant ovarian cancer, we found SENP1 deficiency or treatment by SENP1 inhibitor Momordin Ic significantly overcomes platinum-resistance of ovarian cancer. Thus, this study not only identifies a novel mechanism regulating JAK2 activity, but also provides with a potential approach to treat platinum-resistant ovarian cancer by targeting SENP1/JAK2 pathway.

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Correction to Overcoming Ovarian Cancer Drug Resistance with a Cold Responsive Nanomaterial

ACS Central Science ◽

10.1021/acscentsci.1c00530 ◽

2021 ◽

Author(s):

Hai Wang ◽

Pranay Agarwal ◽

Gang Zhao ◽

Guang Ji ◽

Christopher M. Jewell ◽

...

Keyword(s):

Ovarian Cancer ◽

Drug Resistance ◽

Cancer Drug ◽

Cancer Drug Resistance

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Frontline Maintenance Treatment for Ovarian Cancer

Current Oncology Reports ◽

10.1007/s11912-021-01088-w ◽

2021 ◽

Vol 23 (8) ◽

Author(s):

Osnat Elyashiv ◽

Yien Ning Sophia Wong ◽

Jonathan A. Ledermann

Keyword(s):

Ovarian Cancer ◽

Drug Resistance ◽

Dna Repair ◽

Maintenance Treatment ◽

Advanced Disease ◽

Disease Recurrence ◽

Primary Treatment ◽

New Paradigm ◽

Maintenance Strategies ◽

Advanced Epithelial Ovarian Cancer

Abstract Purpose of Review Advanced epithelial ovarian cancer remains the most lethal gynaecological cancer. Most patients with advanced disease will relapse within 3 years after primary treatment with surgery and chemotherapy. Recurrences become increasing difficult to treat due to the emergence of drug resistance and 5-year survival has changed little over the last decade. Maintenance treatment, here defined as treatment given beyond primary chemotherapy, can both consolidate the response and prolong the control of disease which is an approach to improve survival. Recent Findings Here we review maintenance strategies such as targeting angiogenesis, interference of DNA repair through inhibition of PARP, combinations of targeting agents, and immunotherapy and hormonal therapy. Summary Much has been learnt from the success and challenges of these treatments that have in the last few years which led to significant reduction in disease recurrence, changed the guidelines for treatment, and established a new paradigm for the treatment of ovarian cancer.

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Extracellular Matrix Proteins Expression Profiling in Chemoresistant Variants of the A2780 Ovarian Cancer Cell Line

BioMed Research International ◽

10.1155/2014/365867 ◽

2014 ◽

Vol 2014 ◽

pp. 1-9 ◽

Cited By ~ 38

Author(s):

Radosław Januchowski ◽

Piotr Zawierucha ◽

Marcin Ruciński ◽

Michał Nowicki ◽

Maciej Zabel

Keyword(s):

Ovarian Cancer ◽

Extracellular Matrix ◽

Drug Resistance ◽

Cell Line ◽

Cancer Cell ◽

Ovarian Cancer Cell ◽

Ovarian Cancer Cell Line ◽

Cancer Cell Line ◽

Altered Expression ◽

Expression Levels

Ovarian cancer is the leading cause of death among gynaecological malignancies. Extracellular matrix (ECM) can affect drug resistance by preventing the penetration of the drug into cancer cells and increased resistance to apoptosis. This study demonstrates alterations in the expression levels of ECM components and related genes in cisplatin-, doxorubicin-, topotecan-, and paclitaxel-resistant variants of the A2780 ovarian cancer cell line. Affymetrix Gene Chip Human Genome Array Strips were used for hybridisations. The genes that had altered expression levels in drug-resistant sublines were selected and filtered by scatter plots. The genes that were up- or downregulated more than fivefold were selected and listed. Among the investigated genes, 28 genes were upregulated, 10 genes were downregulated, and two genes were down- or upregulated depending on the cell line. Between upregulated genes 12 were upregulated very significantly—over 20-fold. These genes included COL1A2, COL12A1, COL21A1, LOX, TGFBI, LAMB1, EFEMP1, GPC3, SDC2, MGP, MMP3, and TIMP3. Four genes were very significantly downregulated: COL11A1, LAMA2, GPC6, and LUM. The expression profiles of investigated genes provide a preliminary insight into the relationship between drug resistance and the expression of ECM components. Identifying correlations between investigated genes and drug resistance will require further analysis.

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