RESUMO
Radiation therapy (RT) is an effective local treatment for unresectable hepatocellular carcinoma (HCC), but there are currently no predictive biomarkers to guide treatment decision for RT or adjuvant systemic drugs to be combined with RT for HCC patients. Previously, we reported that extracts of the marine sponge Agelas sp. may contain a natural radiosensitizer for HCC treatment. In this study, we isolated (-)-agelamide D from Agelas extract and investigated the mechanism underlying its radiosensitization. (-)-Agelamide D enhanced radiation sensitivity of Hep3B cells with decreased clonogenic survival and increased apoptotic cell death. Furthermore, (-)-agelamide D increased the expression of protein kinase RNA-like endoplasmic reticulum kinase/inositol-requiring enzyme 1α/activating transcription factor 4 (PERK/eIF2α/ATF4), a key pathway of the unfolded protein response (UPR) in multiple HCC cell lines, and augmented radiation-induced UPR signaling. In vivo xenograft experiments confirmed that (-)-agelamide D enhanced tumor growth inhibition by radiation without systemic toxicity. Immunohistochemistry results showed that (-)-agelamide D further increased radiation-induced ATF4 expression and apoptotic cell death, which was consistent with our in vitro finding. Collectively, our results provide preclinical evidence that the use of UPR inducers such as (-)-agelamide D may enhance the efficacy of RT in HCC management.
Assuntos
Carcinoma Hepatocelular/radioterapia , Alcaloides Diterpenos/farmacologia , Neoplasias Hepáticas/radioterapia , Radiossensibilizantes/farmacologia , Agelas/química , Animais , Linhagem Celular Tumoral , Alcaloides Diterpenos/isolamento & purificação , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Radiossensibilizantes/isolamento & purificação , Resposta a Proteínas não Dobradas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Discovering anticancer drugs that do not have adverse side effects has been a developing research field worldwide in recent decades. In this work, four previously undescribed cytotoxic diterpenoids were isolated from the aerial parts of Isodon excisoides. Interestingly, these four diterpenoids were two pairs of tautomers that were first reported in plants. Their structures were further elucidated using various spectroscopic methods. The tautomerization phenomenon and mechanism for these two pairs of tautomers were emphatically described. The theoretical simulation results indicated that the diterpene tautomerization is greatly related to certain factors, including the existence of a transition state, the change of bond length and the level of conversion energy; the tautomerization for the two pairs of tautomers is mainly caused by proton transfer. For bioassays, the cytotoxicities of the tautomers against five human cancer cell lines were also investigated. The results indicated that each of the four diterpenoids showed significant cytotoxicity in at least three cell lines and could serve as potential anticancer agents for further investigation.
Assuntos
Antineoplásicos/química , Neoplasias do Colo/tratamento farmacológico , Alcaloides Diterpenos/química , Antineoplásicos/isolamento & purificação , Antineoplásicos/farmacologia , Apoptose , Alcaloides Diterpenos/isolamento & purificação , Alcaloides Diterpenos/farmacologia , Descoberta de Drogas , Células HCT116 , Humanos , Isodon , Estrutura Molecular , Análise EspectralRESUMO
Ten new prenylated indole diterpene alkaloids, tolypocladin A-J (1-10), including four chlorinated metabolites, have been isolated from a culture of a mine-soil-derived fungus, Tolypocladium sp. XL115. The structures and absolute configurations of 1-10 were determined by spectroscopic analysis, ECD calculations, and comparison with known compounds. Compounds 1 and 8 displayed significant antimicrobial activities. In addition, compound 1 also showed weak cytotoxic activity against all tested human cancer cell lines and suppressed the growth and viability of the patient-derived HCC cells T1224.