Ursolic acid inhibits proliferation and reverses drug resistance of ovarian cancer stem cells by downregulating ABCG2 through suppressing the expression of hypoxia-inducible factor-1α in vitro

Human ovarian cancer stem cells (HuOCSCs) are the main source of ovarian cancer recurrence, metastasis, and drug resistance. Superparamagnetic iron oxide nanoparticles (SPIONs) are well-known nucleic acid or drug carriers owing to their controllable properties, superior stability, and easy modification. However, whether SPIONs can inhibit the activity of HuOCSCs by inducing ferroptosis remains unclear. In the present study, we isolated CD44+ /CD133+ HuOCSCs from tumours of four patients with clear cell ovarian cancer and added 0.2 mM SPIONs for mixed culture. Transmission electron microscopy showed that SPION-treated HuOCSCs contained multiple high-density electron clouds. Prussian blue staining showed high concentrations of iron ions in the cells. In vitro , SPIONs treatment of HuOCSCs inhibited cell proliferation, migration, and soft agar clone formation, weakened their resistance to multiple chemotherapeutics, and induced cell death. In vivo , SPIONs pretreatment of HuOCSCs significantly reduced their tumour-forming ability and induced angiogenesis in nude mice. Further, SPIONs induced the accumulation of reactive oxygen species in HuOCSCs and induced oxidative stress. qPCR analysis indicated that SPIONs-treated HuOCSCs had reduced expression of tumour stem cell markers (CD117, NANOG, CD133, and SOX2), cell proliferation factors (KI67, CCND), autophagy-related factors (ATG3, ATG5, MAP1ALC3a, MAP1ALC3b, and MAP1ALC3c), and certain negative regulators of ferroptosis, while the mRNA expression levels of cell death-related proteins (BAK1 and BID), and certain positive regulators of ferroptosis were significantly increased. Overall, our findings suggest that SPIONs induce oxidative stress and decrease autophagy activity in ovarian cancer stem cells, activate ferroptosis, and inhibit their proliferation, invasion, drug resistance, and tumorigenic ability.

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

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1421365112 ◽

2015 ◽

Vol 112 (14) ◽

pp. 4411-4416 ◽

Cited By ~ 99

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.

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Abstract 118: Immuno-modulation of macrophages by ovarian cancer stem cells in an in vitro 3D spheroid platform

10.1158/1538-7445.am2018-118 ◽

2018 ◽

Author(s):

Shreya Raghavan ◽

Geeta Mehta

Keyword(s):

Ovarian Cancer ◽

Stem Cells ◽

Cancer Stem Cells ◽

Ovarian Cancer Stem Cells

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Ovarian cancer stem cells and their role in drug resistance

The International Journal of Biochemistry & Cell Biology ◽

10.1016/j.biocel.2018.11.012 ◽

2019 ◽

Vol 106 ◽

pp. 117-126 ◽

Cited By ~ 10

Author(s):

Zalitha Pieterse ◽

Monica Angelica Amaya-Padilla ◽

Terence Singomat ◽

Mudra Binju ◽

Bau Dilam Madjid ◽

...

Keyword(s):

Ovarian Cancer ◽

Stem Cells ◽

Drug Resistance ◽

Cancer Stem Cells ◽

Ovarian Cancer Stem Cells

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

Cancers ◽

10.3390/cancers11111678 ◽

2019 ◽

Vol 11 (11) ◽

pp. 1678 ◽

Cited By ~ 6

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.

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