Exploitation of a novel phenothiazine derivative for its anti-cancer activities in malignant glioblastoma

Omoruyi, Sylvester I.; Ekpo, Okobi Eko; Semenya, Dorothy; Jardine, Anwar; Prince, Sharon

doi:10.1007/s10495-020-01594-5

Cited by 33 publications

(31 citation statements)

References 71 publications

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“…Cyclin D1 plays crucial roles in the progression of cells through the S and G2/M phases ( 21 ), and it is amplified and overexpressed in numerous cancers ( 22 ). Results from western blot analysis revealed that ASIC1a negatively regulated cyclin D1.…”

Section: Resultsmentioning

confidence: 99%

Regulation of gliomagenesis and stemness through acid sensor ASIC1a

et al. 2021

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Glioblastoma multiforme (GBM) is the most prevalent and aggressive type of adult gliomas. Despite intensive therapy including surgery, radiation, and chemotherapy, invariable tumor recurrence occurs, which suggests that glioblastoma stem cells (GSCs) render these tumors persistent. Recently, the induction of GSC differentiation has emerged as an alternative method to treat GBM, and most of the current studies aim to convert GSCs to neurons by a combination of transcriptional factors. As the tumor microenvironment is typically acidic due to increased glycolysis and consequently leads to an increased production of lactic acid in tumor cells, in the present study, the role of acid-sensing ion channel 1a (ASIC1a), an acid sensor, was explored as a tumor suppressor in gliomagenesis and stemness. The bioinformatics data from The Cancer Genome Atlas revealed that ASIC1 expression levels in GBM tumor tissues were lower than those in normal brain, and glioma patients with high ASIC1 expression had longer survival than those with low ASIC1 expression. Our immunohistochemistry data from tissue microarray revealed that ASIC1a expression was negatively associated with glioma grading. Functional studies revealed that the downregulation of ASIC1a promoted glioma cell proliferation and invasion, while upregulation of ASIC1a inhibited their proliferation and invasion. Furthermore, ASIC1a suppressed growth and proliferation of glioma cells through G1/S arrest and apoptosis induction. Mechanistically, ASIC1a negatively modulated glioma stemness via inhibition of the Notch signaling pathway and GSC markers CD133 and aldehyde dehydrogenase 1. ASIC1a is a tumor suppressor in gliomagenesis and stemness and may serve as a promising prognostic biomarker and target for GBM patients.

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Section: Resultsmentioning

confidence: 99%

Regulation of gliomagenesis and stemness through acid sensor ASIC1a

et al. 2021

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“…Other phenothiazine derivatives such as DS00329 or chlorpromazine have similarly had success in preclinical analysis. DS00329 decreased Cyclin A, B, and D1 protein abundance and increased p21, resulting in G1 phase arrest and apoptosis in U251 and U87 cells [49]. Contrastingly, chlorpromazine only demonstrated efficacy in TMZ resistant cells through inhibition of cytochrome c oxidase (CcO, complex IV) activity.…”

Section: Antipsychoticsmentioning

confidence: 98%

An Alternative Pipeline for Glioblastoma Therapeutics: A Systematic Review of Drug Repurposing in Glioblastoma

Lyne

Yamini

2021

Cancers

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The treatment of glioblastoma (GBM) remains a significant challenge, with outcome for most patients remaining poor. Although novel therapies have been developed, several obstacles restrict the incentive of drug developers to continue these efforts including the exorbitant cost, high failure rate and relatively small patient population. Repositioning drugs that have well-characterized mechanistic and safety profiles is an attractive alternative for drug development in GBM. In addition, the relative ease with which repurposed agents can be transitioned to the clinic further supports their potential for examination in patients. Here, a systematic analysis of PubMed and ClinicalTrials.gov (August 17, 2020) provides a comprehensive review of primary articles and unpublished trials that use repurposed drugs for the treatment of GBM. The findings demonstrate that numerous drug classes that have a range of initial indications have efficacy against preclinical GBM models and that certain agents have shown significant potential for clinical benefit. With examination in randomized, placebo-controlled trials and the targeting of particular GBM subgroups, it is possible that repurposing can be a cost-effective approach to identify agents for use in multimodal anti-GBM strategies.

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“…Table 6 summarizes information about all described autophagy activators undergo ing preclinical investigation. α-Hederin in vitro and in vivo studies on colorectal cancer cells [226] MJ-33 in vitro study on HT-29/5FUR cells [227,229] DS00329 in vitro study on malignant glioblastoma cells [230] MHY2256 endometrial and colorectal cancer treatment [231,232] LCC03 in vitro and in vivo study on castration-resistant prostate cancer [233] CZ415 in vitro and in vivo study on human papillary thyroid carcinoma cells [234] Eriocalyxin B in vitro and in vivo study on breast cancer [235] in vitro study on HT-29/5FUR cells [227,229] DS00329 α-Hederin in vitro and in vivo studies on colorectal cancer cells [226] MJ-33 in vitro study on HT-29/5FUR cells [227,229] DS00329 in vitro study on malignant glioblastoma cells [230] MHY2256 endometrial and colorectal cancer treatment [231,232] LCC03 in vitro and in vivo study on castration-resistant prostate cancer [233] CZ415 in vitro and in vivo study on human papillary thyroid carcinoma cells [234] Eriocalyxin B in vitro and in vivo study on breast cancer [235] in vitro study on malignant glioblastoma cells [230] MHY2256 α-Hederin in vitro and in vivo studies on colorectal cancer cells [226] MJ-33 in vitro study on HT-29/5FUR cells [227,229] DS00329 in vitro study on malignant glioblastoma cells [230] MHY2256 endometrial and colorectal cancer treatment [231,232] LCC03 in vitro and in vivo study on castration-resistant prostate cancer [233] CZ415 in vitro and in vivo study on human papillary thyroid carcinoma cells [234] Eriocalyxin B in vitro and in vivo study on breast cancer [235] endometrial and colorectal cancer treatment [231,…”

Section: Mj-33mentioning

confidence: 99%

Autophagy Modulators in Cancer Therapy

Buzun

Gornowicz

Lesyk

et al. 2021

IJMS

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Autophagy is a process of self-degradation that plays an important role in removing damaged proteins, organelles or cellular fragments from the cell. Under stressful conditions such as hypoxia, nutrient deficiency or chemotherapy, this process can also become the strategy for cell survival. Autophagy can be nonselective or selective in removing specific organelles, ribosomes, and protein aggregates, although the complete mechanisms that regulate aspects of selective autophagy are not fully understood. This review summarizes the most recent research into understanding the different types and mechanisms of autophagy. The relationship between apoptosis and autophagy on the level of molecular regulation of the expression of selected proteins such as p53, Bcl-2/Beclin 1, p62, Atg proteins, and caspases was discussed. Intensive studies have revealed a whole range of novel compounds with an anticancer activity that inhibit or activate regulatory pathways involved in autophagy. We focused on the presentation of compounds strongly affecting the autophagy process, with particular emphasis on those that are undergoing clinical and preclinical cancer research. Moreover, the target points, adverse effects and therapeutic schemes of autophagy inhibitors and activators are presented.

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Exploitation of a novel phenothiazine derivative for its anti-cancer activities in malignant glioblastoma

Cited by 33 publications

References 71 publications

Regulation of gliomagenesis and stemness through acid sensor ASIC1a

Regulation of gliomagenesis and stemness through acid sensor ASIC1a

An Alternative Pipeline for Glioblastoma Therapeutics: A Systematic Review of Drug Repurposing in Glioblastoma

Autophagy Modulators in Cancer Therapy

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