Hypoxia-activated cytotoxicity of benznidazole against clonogenic tumor cells

Li, Quhuan; Lin, Qun; Yun, Zhong

doi:10.1080/15384047.2016.1250988

Cited by 7 publications

(4 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The clonogenic assay is based on our previously published protocols [ 22 , 28 ]. Briefly, tumor cells were plated at 600 cells/well for MDA-MB-231 cells and at 1000 cells/well for MCF7 cells in 6-well plates and incubated for 10 to 14 days.…”

Section: Methodsmentioning

confidence: 99%

The hypoxic tumor microenvironment in vivo selects the cancer stem cell fate of breast cancer cells

et al. 2018

Self Cite

View full text Add to dashboard Cite

BackgroundTumor hypoxia is an independent prognostic factor associated with poor patient survival. Emerging evidence suggests that hypoxia can potentially maintain or enhance the stem cell phenotype of both normal stem cells and cancer cells. However, it remains to be determined whether cell fate is regulated in vivo by the hypoxic tumor microenvironment (TME).MethodsWe established a hypoxia-sensing xenograft model to identify hypoxic tumor cell in vivo primarily using human breast cancer cell lines MDA-MB-231 and MCF7. Hypoxic tumor cells were identified in situ by fluorescence of green fluorescence protein. They were further isolated from xenografts, purified and sorted by flow cytometry for detailed analysis of their stem cell characteristics.ResultsWe have found that hypoxic tumor cells freshly isolated from xenografts contain increased subpopulations of tumor cells with cancer stem cell (CSC)-like characteristics. The CSC characteristics of the hypoxic tumor cells are further enhanced upon re-implantation in vivo, whereas secondary xenografts derived from the non-hypoxic tumor cells remain similar to the primary xenografts. Interestingly, the phenotypes exhibited by the hypoxic tumor cells are stable and remain distinctively different from those of the non-hypoxic tumor cells isolated from the same tumor mass even when they are maintained under the same ambient culture conditions. Mechanistically, the PI3K/AKT pathway is strongly potentiated in the hypoxic tumor cells and is required to maintain the CSC-like phenotype. Importantly, the differential cell fates between hypoxic and non-hypoxic tumor cells are only found in tumor cells isolated from the hypoxic TME in vivo and are not seen in tumor cells treated by hypoxia in vitro alone.ConclusionsThese previously unknown observations suggest that the hypoxic TME may promote malignant progression and therapy resistance by coordinating induction, selection and/or preferential maintenance of the CSC-like phenotype in tumor cells.Electronic supplementary materialThe online version of this article (10.1186/s13058-018-0944-8) contains supplementary material, which is available to authorized users.

show abstract

Section: Methodsmentioning

confidence: 99%

The hypoxic tumor microenvironment in vivo selects the cancer stem cell fate of breast cancer cells

et al. 2018

Self Cite

View full text Add to dashboard Cite

show abstract

“…The clonogenic assay is based on our previously published protocols 52,54 . Briefly, tumor cells were plated at 600 cells/well for MDA-MB-231 cells and at 1000 cells/well for SK-N-BE(2)C cells in 6-well plates and incubated for 10 to 14 days.…”

Section: Methodsmentioning

confidence: 99%

BRCA1 regulates the cancer stem cell fate of breast cancer cells in the context of hypoxia and histone deacetylase inhibitors

Kim

Lin

Yun

2019

Sci Rep

Self Cite

View full text Add to dashboard Cite

Cancer cell stemness is essential for enabling malignant progression and clonal evolution. Cancer cell fate is likely determined by complex mechanisms involving both cell-intrinsic pathways and stress signals from tumor microenvironment. In this study, we examined the role of the tumor suppressor BRCA1 and hypoxia in the regulation of cancer cell stemness using genetically matched breast cancer cell lines. We have found that BRCA1, a multifunctional protein involved in DNA repair and epigenetic regulation, plays a critical role in the regulation of cancer stem cell (CSC)-like characteristics. Reconstitution of BRCA1 resulted in significant decrease of the CSC-like populations in breast cancer cells whereas down-regulation of BRCA1 resulted in significant increase of the CSC-like populations. Furthermore, the BRCA1-reconstituted tumor cells are more sensitive to the histone deacetylase (HDAC) inhibitor-induced loss of stemness than the BRCA1-deficient cells are. Surprisingly, hypoxia preferentially blocks HDAC inhibitor-induced differentiation of the BRCA1-reconstituted breast cancer cells. In light of the increasing numbers of clinical trials involving HDAC inhibitors in human cancers, our observations strongly suggest that the BRCA1 status and tumor hypoxia should be considered as potentially important clinical parameters that may affect the therapeutic efficacy of HDAC inhibitors.

show abstract

“…While benznidazole has been found to be mutagenic and associated with lymphomas in animal studies (Teixeira et al, 1990), others have observed that the compound caused a reduction in nitric oxide synthesis in treated infected mice; consequently, this contributed to protect against T. cruzi-induced oxidative DNA damage, minimizing parasite-induced genotoxicity (Ribeiro et al, 2007). Li et al (2016a) have found that benznidazole is a hypoxiaactivated cytotoxin that can specifically kill clonogenic tumor cells that are under severe hypoxic conditions or tumor-initiating cancer cells It probably acts by inducing double-strand breaks, just as on T. cruzi DNA; the same has also been reported for nifurtimox (Li et al, 2017). In addition, some clinical observations do not indicate modifications in the incidence of neoplasms in CD patients treated with benznidazole (Andrade et al, 2003).…”

Section: Pharmacological Intervention For Chagas Disease and Cancermentioning

confidence: 99%

Trypanosoma cruzi, Chagas disease and cancer: putting together the pieces of a complex puzzle

Kaufman,

Farré,

Biscari

et al. 2023

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

Considering the extensive and widespread impact on individuals, cancer can presently be categorized as a pandemic. In many instances, the development of tumors has been linked to endemic microbe infections. Among parasitic infections, Trypanosoma cruzi stands out as one of the most extensively discussed protozoans in the literature that explores the association between diseases of parasite origin and cancer. However, the effective association remains an unsolved paradox. Both the parasite, along with protozoan-derived molecules, and the associated antiparasitic immune response can induce alterations in various host cell pathways, leading to modifications in cell cycle, metabolism, glycosylation, DNA mutations, or changes in neuronal signaling. Furthermore, the presence of the parasite can trigger cell death or a senescent phenotype and modulate the immune system, the metastatic cascade, and the formation of new blood vessels. The interaction among the parasite (and its molecules), the host, and cancer undoubtedly encompasses various mechanisms that operate differentially depending on the context. Remarkably, contrary to expectations, the evidence tilts the balance toward inhibiting tumor growth or resisting tumor development. This effect is primarily observed in malignant cells, rather than normal cells, indicating a selective or specific component. Nevertheless, nonspecific bystander mechanisms, such as T. cruzi’s adjuvancy or the presence of proinflammatory cytokines, may also play a significant role in this phenomenon. This work aims to elucidate this complex scenario by synthesizing the main findings presented in the literature and by proposing new questions and answers, thereby adding pieces to this challenging puzzle.

show abstract

Hypoxia-activated cytotoxicity of benznidazole against clonogenic tumor cells

Cited by 7 publications

References 38 publications

The hypoxic tumor microenvironment in vivo selects the cancer stem cell fate of breast cancer cells

The hypoxic tumor microenvironment in vivo selects the cancer stem cell fate of breast cancer cells

BRCA1 regulates the cancer stem cell fate of breast cancer cells in the context of hypoxia and histone deacetylase inhibitors

Trypanosoma cruzi, Chagas disease and cancer: putting together the pieces of a complex puzzle

Contact Info

Product

Resources

About