scholarly journals Enhanced expression of DNA polymerase eta contributes to cisplatin resistance of ovarian cancer stem cells

2015 ◽  
Vol 112 (14) ◽  
pp. 4411-4416 ◽  
Author(s):  
Amit Kumar Srivastava ◽  
Chunhua Han ◽  
Ran Zhao ◽  
Tiantian Cui ◽  
Yuntao Dai ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Dna Polymerase ◽  
Ovarian Cancer Stem Cells ◽  
Primary Tumors ◽  
Tumor Relapse ◽  
Induced Apoptosis

Cancer stem cells (CSCs) with enhanced tumorigenicity and chemoresistance are believed to be responsible for treatment failure and tumor relapse in ovarian cancer patients. However, it is still unclear how CSCs survive DNA-damaging agent treatment. Here, we report an elevated expression of DNA polymerase η (Pol η) in ovarian CSCs isolated from both ovarian cancer cell lines and primary tumors, indicating that CSCs may have intrinsically enhanced translesion DNA synthesis (TLS). Down-regulation of Pol η blocked cisplatin-induced CSC enrichment both in vitro and in vivo through the enhancement of cisplatin-induced apoptosis in CSCs, indicating that Pol η-mediated TLS contributes to the survival of CSCs upon cisplatin treatment. Furthermore, our data demonstrated a depletion of miR-93 in ovarian CSCs. Enforced expression of miR-93 in ovarian CSCs reduced Pol η expression and increased their sensitivity to cisplatin. Taken together, our data suggest that ovarian CSCs have intrinsically enhanced Pol η-mediated TLS, allowing CSCs to survive cisplatin treatment, leading to tumor relapse. Targeting Pol η, probably through enhancement of miR-93 expression, might be exploited as a strategy to increase the efficacy of cisplatin treatment.

scholarly journals The Metabolic Inhibitor CPI-613 Negates Treatment Enrichment of Ovarian Cancer Stem Cells

Cancers ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 1678 ◽  
Author(s):  
Chiara Bellio ◽  
Celeste DiGloria ◽  
David R. Spriggs ◽  
Rosemary Foster ◽  
Whitfield B. Growdon ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Treatment Strategies ◽  
Tca Cycle ◽  
Metabolic Inhibitor ◽  
Ovarian Cancer Stem Cells ◽  
Platinum Resistant

One of the most significant therapeutic challenges in the treatment of ovarian cancer is the development of recurrent platinum-resistant disease. Cancer stem cells (CSCs) are postulated to contribute to recurrent and platinum-resistant ovarian cancer (OvCa). Drugs that selectively target CSCs may augment the standard of care cytotoxics and have the potential to prevent and/or delay recurrence. Increased reliance on metabolic pathway modulation in CSCs relative to non-CSCs offers a possible therapeutic opportunity. We demonstrate that treatment with the metabolic inhibitor CPI-613 (devimistat, an inhibitor of tricarboxylic acid (TCA) cycle) in vitro decreases CD133+ and CD117+ cell frequency relative to untreated OvCa cells, with negligible impact on non-CSC cell viability. Additionally, sphere-forming capacity and tumorigenicity in vivo are reduced in the CPI-613 treated cells. Collectively, these results suggest that treatment with CPI-613 negatively impacts the ovarian CSC population. Furthermore, CPI-613 impeded the unintended enrichment of CSC following olaparib or carboplatin/paclitaxel treatment. Collectively, our results suggest that CPI-613 preferentially targets ovarian CSCs and could be a candidate to augment current treatment strategies to extend either progression-free or overall survival of OvCa.

scholarly journals Metformin targets ovarian cancer stem cells in vitro and in vivo

2012 ◽  
Vol 127 (2) ◽  
pp. 390-397 ◽  
Author(s):  
Jessica J. Shank ◽  
Kun Yang ◽  
Jacob Ghannam ◽  
Lourdes Cabrera ◽  
Carolyn J. Johnston ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Ovarian Cancer Stem Cells

scholarly journals TRX-E-002-1 Induces c-Jun–Dependent Apoptosis in Ovarian Cancer Stem Cells and Prevents Recurrence In Vivo

2016 ◽  
Vol 15 (6) ◽  
pp. 1279-1290 ◽  
Author(s):  
Ayesha B. Alvero ◽  
Andrew Heaton ◽  
Eydis Lima ◽  
Mary Pitruzzello ◽  
Natalia Sumi ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Ovarian Cancer Stem Cells

Targeting cancer stem cells with a pan-BCL-2 inhibitor in preclinical and clinical settings in patients with gastroesophageal carcinoma

Gut ◽  
2021 ◽  
pp. gutjnl-2020-321175
Author(s):  
Shumei Song ◽  
Qiongrong Chen ◽  
Yuan Li ◽  
Guang Lei ◽  
Ailing Scott ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Antitumour Activity ◽  
Clinical Specimen ◽  
Therapy Resistance ◽  
In Vivo Studies ◽  
Induced Apoptosis

ObjectiveGastro-oesophageal cancers (GEC) are resistant to therapy and lead to poor prognosis. The cancer stem cells (CSCs) and antiapoptotic pathways often confer therapy resistance. We sought to elucidate the antitumour action of a BCL-2 inhibitor, AT101 in GEC in vitro, in vivo and in a clinical trial.MethodsExtensive preclinical studies in vitro and in vivo were carried out to establish the mechanism action of AT101 on targeting CSCs and antiapoptotic proteins. A pilot clinical trial in patients with GEC was completed with AT-101 added to standard chemoradiation.ResultsOverexpression of BCL-2 and MCL-1 was noted in gastric cancer tissues (GC). AT-101 induced apoptosis, reduced proliferation and tumour sphere formation in MCL-1/BCL-2 high GC cells. Interestingly, AT101 dramatically downregulated genes (YAP-1/Sox9) that control CSCs in GEC cell lines regardless of BCL-2/MCL-1 expression. Addition of docetaxel to AT-101 amplified its antiproliferation and induced apoptosis effects. In vivo studies confirmed the combination of AT101 and docetaxel demonstrated stronger antitumour activity accompanied with significant decrease of CSCs biomarkers (YAP1/SOX9). In a pilot clinical trial, 13 patients with oesophageal cancer (EC) received AT101 orally concurrently with chemoradiation. We observed dramatic clinical complete responses and encouraging overall survival in these patients. Clinical specimen analyses revealed that AT-101 dramatically reduced the expression of CSCs genes in treated EC specimens indicating antitumour activity of AT101 relies more on its anti-CSCs activity.ConclusionsOur preclinical and clinical data suggest that AT-101 overcomes resistance by targeting CSCs pathways suggesting a novel mechanism of action of AT101 in patients with GEC.

scholarly journals Calcium Channels as Novel Therapeutic Targets for Ovarian Cancer Stem Cells

2020 ◽  
Vol 21 (7) ◽  
pp. 2327 ◽  
Author(s):  
Heejin Lee ◽  
Jun Woo Kim ◽  
Dae Kyung Kim ◽  
Dong Kyu Choi ◽  
Seul Lee ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Calcium Channel ◽  
Calcium Channel Blockers ◽  
Cancer Recurrence ◽  
Channel Blockers ◽  
Ovarian Cancer Stem Cells ◽  
Induced Apoptosis ◽  
Novel Therapeutic

Drug resistance in epithelial ovarian cancer (EOC) is reportedly attributed to the existence of cancer stem cells (CSC), because in most cancers, CSCs still remain after chemotherapy. To overcome this limitation, novel therapeutic strategies are required to prevent cancer recurrence and chemotherapy-resistant cancers by targeting cancer stem cells (CSCs). We screened an FDA-approved compound library and found four voltage-gated calcium channel blockers (manidipine, lacidipine, benidipine, and lomerizine) that target ovarian CSCs. Four calcium channel blockers (CCBs) decreased sphere formation, viability, and proliferation, and induced apoptosis in ovarian CSCs. CCBs destroyed stemness and inhibited the AKT and ERK signaling pathway in ovarian CSCs. Among calcium channel subunit genes, three L- and T-type calcium channel genes were overexpressed in ovarian CSCs, and downregulation of calcium channel genes reduced the stem-cell-like properties of ovarian CSCs. Expressions of these three genes are negatively correlated with the survival rate of patient groups. In combination therapy with cisplatin, synergistic effect was shown in inhibiting the viability and proliferation of ovarian CSCs. Moreover, combinatorial usage of manidipine and paclitaxel showed enhanced effect in ovarian CSCs xenograft mouse models. Our results suggested that four CCBs may be potential therapeutic drugs for preventing ovarian cancer recurrence.

Abstract 3056: Human ovarian cancer stem cells: In vitro cultivation and characterization

2014 ◽  
Author(s):  
Tatsuya Ishiguro ◽  
Hirokazu Ohata ◽  
Hitoshi Nakagama ◽  
Koji Okamoto ◽  
Kenichi Tanaka ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
In Vitro Cultivation ◽  
Human Ovarian Cancer ◽  
Ovarian Cancer Stem Cells
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