A Role for Acyclic Retinoid in the Chemoprevention of Hepatocellular Carcinoma: Therapeutic Strategy Targeting Phosphorylated Retinoid X Receptor-α

Sakai, Hidetaka; Shimizu, Masahito; Moriwaki, Hisataka

doi:10.3390/diseases2030226

Cited by 3 publications

(2 citation statements)

References 88 publications

(164 reference statements)

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“…It releases cytochrome c, which activates caspase-9 then cleaves caspases-3, -6, and -7, thereby affecting morphological and biochemical features of apoptosis with the intrinsic pathway of late apoptosis, including chromatin condensation, chromatin margination, and nuclear fragmentation. These characteristics of late apoptosis were found in C6-GSCs treated with 9-cis RA in this study [ 6 , 14 , 34 ].…”

Section: Discussionsupporting

confidence: 62%

“…The present study showed that combination of 9-cis RA with Met induced a higher percentage of late apoptosis in C6-GSCs than single treatment with 9-cis RA or Met. Met affected the morphology of early apoptosis whereas 9-cis RA bound to RARs, RXRs, and caused DNA fragmentation [ 10 , 21 , 34 ]. Moreover, the mechanism of apoptosis, confirmed by western blot, shows cleaved caspase-3 in Met-, 9-cis +RA- and Met+ 9-cis RA-induced apoptosis.…”

Section: Discussionmentioning

confidence: 99%

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Combination of metformin and 9-cis retinoic acid increases apoptosis in C6 glioma stem-like cells

Songthaveesin

Sanongdej

Limboonreung

et al. 2018

Heliyon

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Glioblastoma (GBM) is the most commonly diagnosed type of brain cancer and the leading cause of brain cancer-related death. GBM contains a subpopulation of tumor-propagating glioblastoma stem-like cells that are thought to drive cancer progression and recurrence. Although several clinical trials are ongoing to explore new chemotherapeutic agents to treat GBM, the use of metformin (Met), a first-line drug for type 2 diabetes mellitus, in cancer remains controversial. Here, we show that combining Met with 9-cis retinoic acid (9-cis RA) reduced the proliferation rate of C6-GSCs (glioblastoma stem-like cells) in vitro. The results of flow cytometric analysis showed that treatment with 9-cis RA for 24 h induced 4.5% early and 38.0% late apoptosis in C6-GSCs. Twenty-four hours of Met treatment induced 23.6% early and 33.5% late apoptosis in C6-GSCs. Combination of Met and 9-cis RA treatment significantly increased both early and late apoptosis to 30.4% and 55.4%, respectively. The present findings suggest that not only 9-cis RA but also Met has the potential to induce early and late apoptotic GSCs death by affecting the functional cytoplasmic and nuclear organelles. At the protein level, there was increased cleaved caspase-3 but decreased procaspase-3 expression in Met-, 9-cis RA- and Met+9-cis RA-treated C6 GSCs, as detected by western blotting. The ratio of cleaved caspase-3/procaspase-3 was 1.6 times higher in Met+9-cis RA-treated groups compared to control. Ultimately, a combination of Met and 9-cis RA might be a possible therapeutic target for the treatment of GBM.

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Section: Discussionsupporting

confidence: 62%