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Parvifloron D-based potential therapy for glioblastoma: Inducing apoptosis via the mitochondria dependent pathway.

ABSTRACT: Glioblastoma (GB) is the most malignant and frequent primary tumor of the central nervous system. The lack of diagnostic tools and the poor prognosis associated with this tumor type leads to restricted and limited options of treatment, namely surgical resection and radio-chemotherapy. However, despite these treatments, in almost all cases, patients experience relapse, leading to survival rates shorter than 5 years (∼15-18 months after diagnosis). Novel therapeutic approaches are urgently required (either by discovering new medicines or by repurposing drugs) to surpass the limitations of conventional treatments and improve patients' survival rate and quality of life. In the present work, we investigated the antitumor potential of parvifloron D (ParvD), a drug lead of natural origin, in a GB cell line panel. This natural drug lead induced G2/M cell cycle arrest and apoptosis via activation of the intrinsic mitochondria-dependent pathway. Moreover, the necessary doses of ParvD to induce pronounced inhibitory effects were substantially lower than that of temozolomide (TMZ, first-line treatment) required to promote comparable effects. Therefore, ParvD may have the potential to overcome the resistance related to TMZ and contribute to the pursuit of hopeful treatments based on ParvD as a drug lead for future chemotherapeutics.

SUBMITTER: Magalhaes M

PROVIDER: S-EPMC9605735 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Parvifloron D-based potential therapy for glioblastoma: Inducing apoptosis <i>via</i> the mitochondria dependent pathway.

Magalhães Mariana M Domínguez-Martín Eva María EM Jorge Joana J Gonçalves Ana Cristina AC Díaz-Lanza Ana María AM Manadas Bruno B Efferth Thomas T Rijo Patrícia P Cabral Célia C

Frontiers in pharmacology 20221012

Glioblastoma (GB) is the most malignant and frequent primary tumor of the central nervous system. The lack of diagnostic tools and the poor prognosis associated with this tumor type leads to restricted and limited options of treatment, namely surgical resection and radio-chemotherapy. However, despite these treatments, in almost all cases, patients experience relapse, leading to survival rates shorter than 5 years (∼15-18 months after diagnosis). Novel therapeutic approaches are urgently require ...[more]

PMID: 36313298

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Project description:Extensive research has been done in the search for innovative treatments against colon adenocarcinomas; however, the incidence rate of patients remains a major cause of cancer-related deaths in Malaysia. Natural bioactive compounds such as curcumin have been substantially studied as an alternative to anticancer drug therapies and have been surmised as a potent agent but, nevertheless, remain deficient due to its poor cellular uptake. Therefore, efforts now have shifted toward mimicking curcumin to synthesize novel compounds sharing similar effects. A synthetic analog, (Z)-3-hydroxy-1-(2-hydroxyphenyl)-3-phenylprop-2-ene-1-one (DK1), was recently synthesized and reported to confer improved bioavailability and selectivity toward human breast cancer cells. This study, therefore, aims to assess the anticancer mechanism of DK1 in relation to the induction of in vitro cell death in selected human colon cancer cell lines. Using the3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide(MTT) assay, the cytotoxicity of DK1 towards HT29 and SW620 cell lines were investigated. Acridine orange/propidium iodide (AO/PI) dual-staining assay and flow cytometry analyses (cell cycle analysis, Annexin/V-FITC and JC-1 assays) were incorporated to determine the mode of cell death. To further determine the mechanism of cell death, quantitative real-time polymerase chain reaction (qRT-PCR) and proteome profiling were conducted. Results from this study suggest that DK1 induced changes in cell morphology, leading to a decrease in cell viability and subsequent induction of apoptosis. DK1 treatment inhibited cell viability and proliferation 48 h post treatment with IC50 values of 7.5 ± 1.6 µM for HT29 cells and 14.5 ± 4.3 µM for SW620 cells, causing cell cycle arrest with increased accumulation of cell populations at the sub-G₀/G₁phaseof 74% and 23%, respectively. Flow cytometry analyses showed that DK1 treatment in cancer cells induced apoptosis, as indicated by DNA fragmentation and depolarization of the mitochondrial membrane. qRT-PCR results show significant upregulation in the expression of caspase-9 in both HT29 and SW620 cell lines, further supporting that cell death induction by DK1 is via an intrinsic pathway. These outcomes, therefore, demonstrate DK1 as a potential anticancer agent for colon adenocarcinoma due to its anti-apoptotic attributes.

Dataset Information

Parvifloron D-based potential therapy for glioblastoma: Inducing apoptosis via the mitochondria dependent pathway.

Publications

Parvifloron D-based potential therapy for glioblastoma: Inducing apoptosis <i>via</i> the mitochondria dependent pathway.

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