JCI-20679 suppresses autophagy and enhances temozolomide-mediated growth inhibition of glioblastoma cells

Ando, Shota; Moyama, Chiami; Kojima, Naoto; Fujita, Mitsugu; Ohta, Kaito; Kohno, Yukina; Ii, Hiromi; Nakata, Susumu

doi:10.1016/j.bbrc.2021.12.113

Cited by 10 publications

(6 citation statements)

References 16 publications

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“…We previously revealed that the thiophene carboxamide analog of solamin (JCI-20679) exhibits potent antitumor activity by inhibiting mitochondrial complex I. [29][30][31][32][33][34][35][36] The pyrimidine analogs 1a-1c were also significantly correlated with mitochondrial complex I inhibitors, suggesting that analogs 1a-1c inhibit cancer cell growth through mitochondrial complex I inhibition. It is unclear why analogs 1a-1c showed higher inhibitory activity than solamin, but the results discussed above suggest that the pyrimidine moiety linked by the amine bond strongly binds to the target molecule in mitochondrial complex I.…”

Section: Resultsmentioning

confidence: 99%

Synthesis of Acetogenin Analogs Comprising Pyrimidine Moieties Linked by Amine Bonds and Their Inhibitory Activity against Human Cancer Cell Lines

et al. 2022

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Here, we synthesized three acetogenin analogs containing pyrimidine moieties linked by amine bonds, which represent the skeleton structure of pyrimidifen, a mitochondrial complex I-inhibiting insecticide. Replacing the pyrimidine moiety linked by the amine bond remarkably enhanced growth-inhibitory activity of the analogs against several human cancer cell lines. Moreover, these analogs selectively and potently inhibited the growth of these human cancer cell lines regardless of the pyrimidine substituents. Furthermore, COMPARE analyses suggested that these analogs inhibited cancer growth by inhibiting mitochondrial complex I. Our study provides insights into the design of acetogenin analogs as novel antitumor agents.

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Section: Resultsmentioning

confidence: 99%

Synthesis of Acetogenin Analogs Comprising Pyrimidine Moieties Linked by Amine Bonds and Their Inhibitory Activity against Human Cancer Cell Lines

et al. 2022

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“…29 Our mitochondrial inhibitor (analog 1), combined with TMZ, synergistically enhanced antitumor activity against glioblastoma in vivo. 22 Therefore, an isobologram analysis of U251 human glioblastoma cells was performed to evaluate whether 2k exhibited a synergistic effect, similar to that of 1, when combined with TMZ. The combination index (CI) values for 2k and TMZ were 0.325 in ED 50 and 0.765 in ED 75 (Figure 5).…”

Section: Synthesis and In Vitro Gsc Inhibitory Activities Of Analogs ...mentioning

confidence: 99%

“…21 Additionally, 1 enhances the antitumor activity of TMZ. 22 However, the synthesis of 1 needs 23 steps, including 16 steps for the preparation of a THF moiety consisting of four asymmetric carbons. This prevents rapid SAR studies.…”

Section: ■ Introductionmentioning

confidence: 99%

“…We had previously studied the SAR of annonaceous acetogenins to develop anticancer agents. − Annonaceous acetogenins are polyketides isolated from Annona plants that grow in tropical and subtropical regions; most contain one to three 2,5-disubstituted tetrahydrofurans (THFs) in the center of the long hydrocarbon chain and an α,β-unsaturated-γ-lactone at the end of the molecule. − The structure of solamin, an acetogenin, is shown in Figure . − Studies have revealed that the mitochondrial complex I inhibitor JCI-20679 ( 1 ), , a solamin analog, showed antitumor activity against glioblastoma by activating AMP-activated protein kinase (AMPK) . Additionally, 1 enhances the antitumor activity of TMZ . However, the synthesis of 1 needs 23 steps, including 16 steps for the preparation of a THF moiety consisting of four asymmetric carbons.…”

Section: Introductionmentioning

confidence: 99%

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Thiophene Carboxamide Analogs with Long Alkyl Chains Comprising Ethylene Glycol Units Inhibit Glioblastoma Cell Proliferation by Activating AMPK

Ohta

Moyama

et al. 2023

J. Med. Chem.

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Glioblastoma is a refractory malignant tumor that requires novel therapeutic strategies for effective treatment. We have previously reported that JCI-20679 (1), an analog of annonaceous acetogenins, shows potent antitumor activity against glioblastomas. However, the synthesis of 1 requires 23 steps, including 16 steps for the preparation of a tetrahydrofuran (THF) moiety. This study reports the design and synthesis of 11 analogs with a triethylene glycol moiety in place of the THF moiety in 1. Among these, the analog 2k with an n-decyl chain exhibited potent inhibitory activity against the growth of glioblastoma stem cells by inhibiting mitochondrial function and synergistically enhancing the effect of temozolomide (TMZ). Furthermore, 2k significantly suppressed tumor growth without critical toxicity in vivo. Hence, this study presents novel potential anticancer agents and a strategy for the development of these agents that can be produced easily.

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“…The most promising treatment of GBM is a combination therapy of radio and chemotherapies (such as temozolomide) [ 13 , 14 , 15 ]. Still, radio or chemotherapies have potential toxicity to the surrounding normal brain [ 12 , 15 , 16 , 17 , 18 , 19 ]. These therapies may contribute to hematological complications, cause fatigue, and are implicated in an increased rate of infections among patients [ 12 , 16 , 17 , 18 ].…”

Section: Introductionmentioning

confidence: 99%

Optimization of Tumor Targeting Gold Nanoparticles for Glioblastoma Applications

et al. 2022

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Glioblastoma brain tumors represent an aggressive form of gliomas that is hallmarked by being extremely invasive and aggressive due to intra and inter-tumoral heterogeneity. This complex tumor microenvironment makes even the newer advancements in glioblastoma treatment less effective long term. In developing newer treatment technologies against glioblastoma, one should tailor the treatment to the tumor microenvironment, thus allowing for a more robust and sustained anti-glioblastoma effect. Here, we present a novel gold nanoparticle therapy explicitly designed for bioactivity against glioblastoma representing U87MG cell lines. We employ standard conjugation techniques to create oligonucleotide-coated gold nanoparticles exhibiting strong anti-glioblastoma behavior and optimize their design to maximize bioactivity against glioblastoma. Resulting nanotherapies are therapy specific and show upwards of 75% inhibition in metabolic and proliferative activity with stark effects on cellular morphology. Ultimately, these gold nanotherapies are a good base for designing more multi-targeted approaches to fighting against glioblastoma.

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JCI-20679 suppresses autophagy and enhances temozolomide-mediated growth inhibition of glioblastoma cells

Cited by 10 publications

References 16 publications

Synthesis of Acetogenin Analogs Comprising Pyrimidine Moieties Linked by Amine Bonds and Their Inhibitory Activity against Human Cancer Cell Lines

Synthesis of Acetogenin Analogs Comprising Pyrimidine Moieties Linked by Amine Bonds and Their Inhibitory Activity against Human Cancer Cell Lines

Thiophene Carboxamide Analogs with Long Alkyl Chains Comprising Ethylene Glycol Units Inhibit Glioblastoma Cell Proliferation by Activating AMPK

Optimization of Tumor Targeting Gold Nanoparticles for Glioblastoma Applications

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