RESUMEN

Aim: Therapy to overcome drug resistance by modulating epidermal growth factor receptor (EGFR) is a viable approach to suppress the proliferation of human non-small cell lung cancer (NSCLC) cells. A previous study demonstrated that the seeds of an aqueous Brucea javanica (BJ) (L.) Merr (Simaroubaceae) extract containing quassinoid mixtures effectively inhibited the growth and alleviated tumorigenesis in H1975 cells of NSCLC by targeting T790M/L858R EGFR. This study aimed to further determine whether the aqueous BJ extract affects the enriched H1975 spheroids in suspension culture and mouse xenograft tumor models. Methods: The spheroids of NSCLC adenocarcinoma H1975 cells were enriched in a serum-free media. The growth rate of sphere propagation by aqueous BJ extract was determined in suspended culture and in colony-formation assay. BJ extract was fed orally to nude mice bearing xenograft tumors. The resected tumors were analyzed by hematoxylin and eosin staining, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay, and proliferating cell nuclear antigen assessment. Various markers were used to determine the pluripotency of tumors from mice treated with different concentrations of BJ extract. Results: BJ extract was demonstrated to be effective against the propagation of the enriched spheroids. In animal models, oral administration of the aqueous BJ extract reduced spheroid tumorigenicity. The alleviated growth of the established xenograft tumors can be attributed to the reduced drug resistance and induced apoptosis without distinct adverse effects. More evidence supports activated apoptotic death attenuated spheroid stemness of tumors. Conclusion: As an effective treatment regime to assuage lung cancer, the indigenous BJ extract promises to obliterate drug resistance and the growth of cancer stem cell tumors from NSCLC cells harboring T790M/L858R EGFR.

RESUMEN

As a practical and safe herbal medicine, the seeds of Brucea javanica (L.) Merr., were used to cure patients suffering from infectious diseases such as malaria. Recent advances revealed that the herb could also be a useful cancer therapy agent. The study demonstrated that aqueous B. javanica (BJ) extract attenuated the growth of human non-small-lung cancer cells bearing mutant L858R/T790M epidermal growth factor receptor (EGFR). The reduced cell viability in H1975 cells was attributed to apoptosis. Transfection of EGFR small hairpin RNA reverted the sensitivities. When nude mice were fed BJ extract, the growth of xenograft tumors, as established by H1975 cells, was suppressed. Additional histological examination and fluorescence analysis of the resected tissues proved that the induced apoptosis mitigated tumor growth. The work proved that the BJ extract exerted its effectiveness by targeting lung cancer cells carrying mutated EGFR while alleviating tumorigenesis. Aqueous BJ extract is a good candidate to overcome drug resistance in patients undergoing target therapy.

Asunto(s)

RESUMEN

Being effective and relatively safe, the traditional Chinese medicinal herb Brucea javanica (BJ) has been valuable in curing patients in East Asia and its nearby regions for years. Recent reports suggested that the medicinal herb possesses broad antitumor activity against various cancer cells. This study evaluated whether low concentrations of BJ aqueous extract inhibited the growth of liver cancer cells. Experiments including flow cytometry and Western blot analysis established the development of apoptotic cell death after treatment. Further experiments evaluated the growth of the enriched spheroids. BJ not only reduced the expression of stem cell markers but also eliminated tumor spheroids by apoptotic death. The findings suggest BJ is a promising supplement to the current therapy regimen and highlight the opportunity of BJ as a practical avenue to suppress the growth of the stem cells in liver cancer.

Asunto(s)

RESUMEN

A number of effective anti-cancer drugs contain either indole or quinoline group. Compounds fused indole and quinoline moieties altogether as indolylquinoline were rarely reported as anti-cancer agents. We reported here that a synthetic indolylquinoline derivative, 3-((7-ethyl-1H-indol-3-yl)-methyl)-2-methylquinoline (EMMQ), inhibited the growth of human non-small cell lung cancer (NSCLC) cells in dose- and time-dependent manners. The cytotoxicity was mediated through apoptotic cell death that began with mitochondrial membrane potential interruption and DNA damage. EMMQ caused transient elevation of p53 that assists in cytochrome c release, cleavage of downstream PARP and procaspase-3 and mitochondria-related apoptosis. The degree of apoptotic cell death depends on the status of tumor suppressor p53 of the target cells. H1299 cells with stable ectopic expression of p53 induced cytotoxicity by disrupting mitochondria functions that differed with those transfected with mutant p53. Knocking-down of p53 attenuated drug effects. EMMQ suppressed the growth of A549 tumor cells in xenograft tumors by exhibiting apoptosis characteristics. Given its small molecular weight acting as an effective p53 regulator in NSCLC cells, EMMQ could be an addition to the current list of lung cancer treatment.

Asunto(s)