Targeting cancer stem cells with p53 modulators

Zhang, Zhan; Liu, Ling; Gomez-Casal, Roberto; Wang, Xinhui; Hayashi, Ryo; Appella, Ettore; Kopelovich, Levy; DeLeo, Albert B.

doi:10.18632/oncotarget.8650

Cited by 18 publications

(11 citation statements)

References 45 publications

(48 reference statements)

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“…The proportions of ALDH high and CD133 +ve cells in the two endometrial cancer cell lines reported here are similar to those in other studies [40,41,42]. This is the first study, however, in which the two populations of cells with cancer stem cell activity have been directly compared at a functional and genetic level.…”

Section: Discussionsupporting

confidence: 88%

Targeting Endometrial Cancer Stem Cell Activity with Metformin Is Inhibited by Patient-Derived Adipocyte-Secreted Factors

Kitson

Rosser

Fischer

et al. 2019

Cancers

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Advanced endometrial cancer continues to have a poor prognosis, due to limited treatment options, which may be further adversely impacted by obesity. Endometrial cancer stem cells have been reported to drive metastasis, chemotherapy resistance and disease relapse, but have yet to be fully characterised and no specific targeted therapies have been identified. Here, we describe the phenotype and genotype of aldehyde dehydrogenase high (ALDHhigh) and CD133+ve endometrial cancer stem cells and how adipocyte secreted mediators block the inhibitory effect of metformin on endometrial cancer stem cell activity. Ishikawa and Hec-1a cell lines were used to characterise ALDHhigh and CD133+ve endometrial cancer cells using flow cytometry, functional sphere assays and quantitative-Polymerase Chain Reaction. The comparative effect of metformin on endometrial cancer stem cell activity and bulk tumour cell proliferation was determined using an Aldefluor and cytotoxicity assay. The impact of adipocyte secreted mediators on metformin response was established using patient-derived conditioned media. ALDHhigh cells demonstrated greater endometrial cancer stem cell activity than CD133+ve cells and had increased expression of stem cell and epithelial-mesenchymal transition genes. Treatment with 0.5–1 mM metformin reduced the proportion and activity of both endometrial cancer stem cell populations (p ≤ 0.05), without affecting cell viability. This effect was, however, inhibited by exposure to patient-derived adipocyte conditioned media. These results indicate a selective and specific effect of metformin on endometrial cancer stem cell activity, which is blocked by adipocyte secreted mediators. Future studies of metformin as an adjuvant therapy in endometrial cancer should be adequately powered to investigate the influence of body mass on treatment response.

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Section: Discussionsupporting

confidence: 88%

Targeting Endometrial Cancer Stem Cell Activity with Metformin Is Inhibited by Patient-Derived Adipocyte-Secreted Factors

Kitson

Rosser

Fischer

et al. 2019

Cancers

View full text Add to dashboard Cite

show abstract

“…The proportions of ALDH high and CD133 +ve cells in the two endometrial cancer cell lines reported here are similar to those in other studies (42)(43)(44). This is the first study, however, in which the two populations of cells with cancer stem cell activity have been directly compared at a functional and genetic level.…”

Section: Discussionsupporting

confidence: 87%

Targeting endometrial cancer stem cell activity with metformin is inhibited by patient-derived adipocyte-secreted factors

Kitson

Rosser

Fischer

et al. 2019

Preprint

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PurposeAdvanced endometrial cancer continues to have a poor prognosis due to limited treatment options, which may be further adversely impacted by obesity. Endometrial cancer stem cells have been reported to drive metastasis, chemotherapy resistance and disease relapse, but have yet to be fully characterised and no specific targeted therapies have been identified. Here, we describe the phenotype and genotype of aldehyde dehydrogenase high (ALDH high ) and CD133 +ve endometrial cancer stem cells and how adipocyte secreted mediators block the inhibitory effect of metformin on endometrial cancer stem cell activity. Experimental designIshikawa and Hec-1a cell lines were used to characterise ALDH high and CD133 +ve endometrial cancer cells using flow cytometry, functional sphere assays and quantitative-Polymerase Chain Reaction. The comparative effect of metformin on endometrial cancer stem cell activity and bulk tumour cell proliferation was determined using an Aldefluor and cytotoxicity assay. The impact of adipocyte secreted mediators on metformin response was established using patient-derived conditioned media. ResultsALDH high cells demonstrated greater endometrial cancer stem cell activity than CD133 +ve cells and had increased expression of stem cell and epithelial-mesenchymal transition genes. Treatment with 0.5-1mM metformin reduced the proportion and activity of both endometrial cancer stem cell populations (p≤0.05), without affecting cell viability. This effect was, however, inhibited by exposure to patient-derived adipocyte conditioned media. ConclusionsThese results indicate a selective and specific effect of metformin on endometrial cancer stem cell activity, which is blocked by adipocyte secreted mediators. Future studies of metformin as an adjuvant therapy in endometrial cancer should be adequately powered to investigate the influence of body mass on treatment response.

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“…Recently, Zhang et al reported that CP significantly reduced cancer stem cell (CSC) content, defined as aldehyde dehydrogenase (ALDH) over-expressed cells, in human breast, endometrial, or pancreas carcinoma cell lines in vitro [ 22 ]. CSCs were identified in various tumors including MM.…”

Section: Discussionmentioning

confidence: 99%

Small molecule CP-31398 induces reactive oxygen species-dependent apoptosis in human multiple myeloma

et al. 2017

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Reactive oxygen species (ROS) are normal byproducts of a wide variety of cellular processes. ROS have dual functional roles in cancer cell pathophysiology. At low to moderate levels, ROS act as signaling transducers to activate cell proliferation, migration, invasion, and angiogenesis. In contrast, high levels of ROS induce cell death. In multiple myeloma (MM), ROS overproduction is the trigger for apoptosis induced by several anticancer compounds, including proteasome inhibitors. However, no drugs for which oxidative stress is the main mechanism of action are currently used for treatment of MM in clinical situations. In this study, we demonstrate that the p53-activating small molecule CP-31398 (CP) effectively inhibits the growth of MM cell lines and primary MM isolates from patients. CP also suppresses the growth of MM xenografts in mice. Mechanistically, CP was found to induce intrinsic apoptosis in MM cells via increasing ROS production. Interestingly, CP-induced apoptosis occurs regardless of the p53 status, suggesting that CP has additional mechanisms of action. Our findings thus indicate that CP could be an attractive candidate for treatment of MM patients harboring p53 abnormalities; this satisfies an unmet clinical need, as such individuals currently have a poor prognosis.

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Targeting cancer stem cells with p53 modulators

Cited by 18 publications

References 45 publications

Targeting Endometrial Cancer Stem Cell Activity with Metformin Is Inhibited by Patient-Derived Adipocyte-Secreted Factors

Targeting Endometrial Cancer Stem Cell Activity with Metformin Is Inhibited by Patient-Derived Adipocyte-Secreted Factors

Targeting endometrial cancer stem cell activity with metformin is inhibited by patient-derived adipocyte-secreted factors

Small molecule CP-31398 induces reactive oxygen species-dependent apoptosis in human multiple myeloma

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