RESUMO
Aim: Certain cancer cells depend on oxidative phosphorylation for survival; thus, inhibiting this process may be a promising treatment strategy. This study explored the structure-activity relationships of the mitochondrial inhibitor N-ethylene glycol-comprising alkyl thiophene-3-carboxamide 3.Methods & results: We synthesized and evaluated 13 analogs (5a-m) with different ethylene glycol units, heterocycles and connecting groups for their growth-inhibitory effects on A549 non-small cell lung cancer cells. We found that increasing the number of ethylene glycol units significantly enhanced inhibitory activity. Some analogs activated adenosine monophosphate-activated protein kinase, similar to 3. Notably, analog 5e, which contains tetraethylene glycol units, significantly inhibited tumor growth in vivo.Conclusion: Analog 5 may be a potential therapeutic agent for non-small cell lung cancer treatment.
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RESUMO
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.
Assuntos
Glioblastoma , Humanos , Glioblastoma/tratamento farmacológico , Glioblastoma/patologia , Proteínas Quinases Ativadas por AMP , Linhagem Celular Tumoral , Tiofenos/farmacologia , Tiofenos/uso terapêutico , Proliferação de Células , Etilenoglicóis/farmacologia , Etilenoglicóis/uso terapêuticoRESUMO
We studied hybrid molecules of annonaceous acetogenins and mitochondrial complex I-inhibiting insecticides to develop a novel anticancer agent. A structure-antitumor activity relationship study focusing on the connecting groups between the heterocycles and the linker moiety bearing the tetrahydrofuran moiety was conducted. Eleven hybrid acetogenins with 1-methylpyrazole instead of γ-lactone were synthesized and their growth inhibitory activities against 39 human cancer cell lines were evaluated. The nitrogen atom at the 2'-position of the linker moiety was essential for inhibiting cancer growth. The 1-methylpyrazole-5-sulfonamide analog showed potent growth inhibition of NCI-H23, a human lung cancer cell line, in a xenograft mouse assay without critical toxicity. Hence, the results of this study may pave the way for the development of novel anticancer agents, with both selective and broad anticancer activities.
RESUMO
The prognosis of glioblastoma, which is the most frequent type of adultonset malignant brain tumor, is extremely poor. Therefore, novel therapeutic strategies are needed. Previous studies report that JCI20679, which is synthesized based on the structure of naturally occurring acetogenin, inhibits mitochondrial complex I and suppresses the growth of various types of cancer cells. However, the efficacy of JCI20679 on glioblastoma stem cells (GSCs) is unknown. The present study demonstrated that JCI20679 inhibited the growth of GSCs derived from a transposon systemmediated murine glioblastoma model more efficiently compared with the growth of differentiationinduced adherent cells, as determined by a trypan blue staining dye exclusion test. The inhibition of proliferation was accompanied by the blockade of cellcycle entry into the Sphase, as assessed by a BrdU incorporation assay. JCI20679 decreased the mitochondrial membrane potential, suppressed the oxygen consumption rate and increased mitochondrial reactive oxygen species generation, indicating that JCI20679 inhibited mitochondrial activity. The mitochondrial inhibition was revealed to increase phosphorylated (phospho)AMPKα levels and decrease nuclear factor of activated Tcells 2 (NFATc2) expression, and was accompanied by a decrease in calcineurin phosphatase activity. Depletion of phosphoAMPKα by knockdown of AMPKß recovered the JCI20679mediated decrease in NFATc2 expression levels, as determined by western blotting and reverse transcriptionquantitative PCR analysis. Overexpression of NFATc2 recovered the JCI20679mediated suppression of proliferation, as determined by a trypan blue staining dye exclusion test. These results suggest that JCI20679 inhibited mitochondrial oxidative phosphorylation, which activated AMPK and reduced NFATc2 expression levels. Moreover, systemic administration of JCI20679 extended the eventfree survival rate in a mouse model transplanted with GSCs. Overall, these results suggested that JCI20679 is a potential novel therapeutic agent against glioblastoma.
Assuntos
Glioblastoma , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Proliferação de Células , Glioblastoma/tratamento farmacológico , Glioblastoma/genética , Glioblastoma/metabolismo , Camundongos , Células-Tronco Neoplásicas/metabolismo , Azul Tripano/metabolismo , Azul Tripano/uso terapêuticoRESUMO
Glioblastoma, a type of brain cancer, is one of the most aggressive and lethal types of malignancy. The present study shows that JCI-20679, an originally synthesized mitochondrial complex I inhibitor, enhances the anti-proliferative effects of suboptimal concentrations of the clinically used chemotherapeutic drug temozolomide in glioblastoma cells. Analysis of the effects of temozolomide combined with JCI-20679 using isobologram and combination index methods demonstrated that the combination had synergistic effects in murine and human glioblastoma cells. We found that JCI-20679 inhibited the temozolomide-mediated induction of autophagy that facilitates cellular survival. The autophagy induced by temozolomide increased ATP production, which confers temozolomide resistance in glioblastoma cells. JCI-20679 blocked temozolomide-mediated increases in ATP levels and increased the AMP/ATP ratio. Furthermore, JCI-20679 enhanced the therapeutic effects of temozolomide in an orthotopic transplantation model of glioblastoma. These results indicate that JCI-20679 may be promising as a novel agent for enhancing the efficacy of temozolomide against glioblastoma.
Assuntos
Autofagia , Glioblastoma , Temozolomida , Animais , Humanos , Trifosfato de Adenosina/metabolismo , Autofagia/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sinergismo Farmacológico , Glioblastoma/patologia , Camundongos SCID , Temozolomida/farmacologiaRESUMO
In a previous study, we found that the thiophene carboxamide solamin analog, which is a mono-tetrahydrofuran annonaceous acetogenin, showed potent antitumor activity through the inhibition of mitochondrial complex I. In this study, we synthesized analogs with short alkyl chains instead of the n-dodecyl group in the tail part. We evaluated their growth inhibitory activities against human cancer cell lines. We found that the alkyl chain in the tail part plays an essential role in their activity.