RESUMEN
AIM: The purpose of this study was to investigate anti-tumor effects and safety of DH332, a new ß-carboline alkaloids derivatives in vitro and in vivo. MATERIALS AND METHODS: The effects of DH332 on human (RAMOS RA.1) and mouse (J558) B lymphoma cell lines were detected using a CCK-8 kit (Cell Counting Kit-8), and apoptosis was detected by flow cytometry with PI/annexinV staining. Western blotting was used to detected caspase-3 and caspase-8. Neurotoxic and anti-tumor effects were evaluated in animal experiments. RESULTS: DH332 exerts a lower neurotoxicity compared with harmine. It also possesses strong antitumor effects against two B cell lymphoma cell lines with low IC50s. Moreover, DH332 could inhibit the proliferation and induce the apoptosis of RAMOS RA.1 and J558 cell lines in a dose-dependent manner. Our results suggest that DH332 triggers apoptosis by mainly activating the caspase signaling pathway. In vivo studies of tumor-bearing BALB/c mice showed that DH332 significantly inhibited growth of J558 xenograft tumors. CONCLUSIONS: DH332 exerts effective antitumor activity in vitro and in vivo, and has the potential to be a promising drug candidate for lymphoma therapy.
Asunto(s)
Carbolinas/farmacología , Caspasa 3/metabolismo , Caspasa 8/metabolismo , Linfoma de Células B/tratamiento farmacológico , Alcaloides/efectos adversos , Alcaloides/farmacología , Animales , Antineoplásicos/efectos adversos , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Carbolinas/efectos adversos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Evaluación Preclínica de Medicamentos , Femenino , Harmina/farmacología , Humanos , Ratones , Ratones Endogámicos BALB C , Transducción de Señal/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The starting material L-tryptophan reacted with 4-chlorobenzaldehyde via Pictet-Spengler condensation and followed by oxidation and decarboxylation to afford the 1-(4-chlorophenyl)-beta-carboline. The intermediate was further reacted with alkyl halogenide by N(9)-alkylation and N2-quaternarization to obtain 12 novel 1-(4-chlorophenyl)-beta-carboline derivatives. The chemical structures of all target compounds were characterized by elemental analyses, MS and 1H NMR spectra. The antitumor activities of the target compounds were evaluated by MTT method. The results demonstrated that N2-quaternarized compounds enhanced the antitumor activity significantly. In particular, compound 15 was found to be the most potent compound with IC50 values lower than 5 micromol x L(-1) against 6 human tumor cells. These results confirmed that the N2-alkyl or aralkyl substituent on the beta-carboline ring played an important role in the modulation of the antitumor activities.