Novel GSH-responsive prodrugs derived from indole-chalcone and camptothecin trigger apoptosis and autophagy in colon cancer.
Bioorg Chem
; 143: 107056, 2024 Feb.
Article
en En
| MEDLINE
| ID: mdl-38183685
ABSTRACT
Antineoplastic agents that target tubulin have shown efficacy as chemotherapeutic drugs, yet they are often constrained by multidrug resistance (MDR) and unwanted side effects. A multi-targeted strategy demonstrates great potency in reducing toxicity and enhancing efficacy and provides an alternative way for attenuating MDR. In this study, a series of dual-targeted anti-cancer agents based on indole-chalcone derivatives and the camptothecin (CPT) scaffold were synthesized. Among them, 14-1 demonstrated superior anti-proliferative activity than its precursor 13-1, CPT or their physical mixtures against tested cancer cells, including multidrug-resistant variants, while exhibited moderate cytotoxicity toward human normal cells. Mechanistic studies revealed that 14-1 acted as a glutathione-responsive prodrug, inducing apoptosis by substantially enhancing intracellular uptake of CPT, inhibiting tubulin polymerization, increasing the accumulation of intracellular reactive oxygen species, and initiating a mitochondrion-dependent apoptotic pathway. Moreover, 14-1 notably induced autophagy and suppressed topoisomerase I activity to further promote apoptosis. Importantly, 14-1 displayed potent inhibitory effect on tumor growth in paclitaxel (PTX)-resistant colorectal cancer (HCT-116/PTX) xenograft models without inducing obvious toxicity compared with CPT- or combo-treated group. These results suggest that 14-1 holds promise as a novel candidate for anti-cancer therapy, particularly in PTX-resistant cancers.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Profármacos
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Neoplasias del Colon
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Chalconas
/
Antineoplásicos
Límite:
Humans
Idioma:
En
Año:
2024
Tipo del documento:
Article