RESUMEN
Multi-drug resistance remains a critical issue in cancer treatment that hinders the effective use of chemotherapeutic drugs. The active components of traditional Chinese medicine have been applied as adjuvants to accentuate the anticancer properties of conventional drugs such as cisplatin. However, their application requires further validation and optimization. This study explored the anticancer activity of ß-elemene, a natural component of traditional Chinese medical formulations. The effect of ß-elemene on the anticancer properties of cisplatin was evaluated in A549 and NCI-H1650 lung cancer cells. Cell apoptosis, stem-like properties, glucose metabolism, multi-drug resistance, and PI3K/AKT/mTOR activation were assessed via flow cytometry, tumorsphere formation, and western blotting. The target genes of ß-elemene were predicted using bioinformatics tools and validated in both cell lines. A xenograft model of lung cancer was established in nude mice to evaluate the combined effects of ß-elemene and cisplatin in vivo. We found that ß-elemene acted synergistically with cisplatin against non-small cell lung cancer cells by promoting apoptosis and impairing glucose metabolism, multi-drug resistance, and stemness maintenance. These effects were mediated by the inhibition of PI3K/AKT/mTOR activation. Bioinformatics analysis revealed that RB1 and TP53 are common target genes associated with lung cancer and ß-elemene. The anti-tumorigenic properties of ß-elemene were confirmed in vivo, wherein ß-elemene, along with cisplatin, significantly suppressed tumor growth in a mouse xenograft model of non-small cell lung cancer. As such, ß-elemene acted as an inhibitor of PI3K/AKT/mTOR signaling and enhanced the anticancer effect of cisplatin by targeting tumor metabolism, chemoresistance, and stem-like behavior. Thus, ß-elemene is an effective anticancer adjuvant agent with potential clinical applications.
RESUMEN
Glioblastoma is the most aggressive cerebral gliomas. Despite advances in therapies, the prognosis is still very poor. Therefore, novel therapeutic strategies are required. As a proteasome inhibitor, bortezomib has shown its efficacy as an active antitumor agent against a variety of tumors. However, inhibition of proteasome activity leads to cell death and also induces cell autophagy, and due to the dual roles of autophagy in the survival and death of tumor cells, the effect of inhibition of autophagy on glioblastoma cells remains to be explored. We therefore assessed whether bortezomib is capable of inducing autophagy, and investigated the antitumor effect of bortezomib combined with autophagy inhibitors on human glioblastoma U251 and U87 cells. Cell viability was measured by MTT assay. The expressions of autophagy and apoptosis-related proteins were determined by Western blot analysis. U251 and U87 cells proliferation was inhibited in a dose-dependent manner. Both apoptosis and autophagy induced by bortezomib were observed in human glioblastoma U87 and U251 cells. However, when U251 and U87 cells were co-treated with bortezomib and autophagy inhibitors 3-MA or Atg7 siRNA, the autophagy inhibitors blocked the autophagy in the cells and resulted in a further inhibition of cell proliferation and a further increase in cell apoptosis as compared with that treated with bortezomib alone. These findings indicated that combination of bortezomib and autophagy inhibitors may shed new light on glioblastoma treatment.
