sirolimus and gambogic-acid

Gambogic acid (GA) is a natural compound with a polyprenylated xanthone structure that has antiinflammatory, antioxidant, and neuroprotective properties and acts as a chemopreventive agent. GA exhibits anti-tumor, antimicrobial, and anti-proliferative effects on cancer cells. In the current study, the effect of GA on phosphoinositide kinase-3 (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway was examined in human U251 glioma cells. Cell viability and apoptosis were evaluated by MTT and Annexin V/PI Double Staining. The expressions of P38, AKT, and mTOR were evaluated by western blot and qRT-PCR, respectively. MagBeads Total RNA Extraction Kit was used to isolate cell tissue RNA. GA decreased the phosphorylation of P38, AKT, and mTOR. Inhibitors of PI3K (LY294002) enhanced the phosphorylation of P38, AKT, and mTOR. GA reduced the phosphorylation of ribosomal protein precursors (Pre) and upstream binding factor (UBF), and insulin-like growth factor I (IGF-1) further enhanced the cell proliferation and expression of Pre and UBF. These results suggested that downregulation of PI3K/AKT/mTOR signaling pathway may be an important mediator in GA-affected ribosomal occurrence in glioma cells.

Topics: 1-Phosphatidylinositol 4-Kinase; Apoptosis; Cell Proliferation; Glioma; Humans; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Xanthones

Gambogic acid (GA) has been shown to inhibit cancer cell proliferation, induce apoptosis, and enhance reactive oxygen species accumulation. However, whether GA could improve multidrug resistance through modulating autophagy has never been explored. We demonstrated that the combination of GA and cisplatin (CDDP) resulted in a stronger growth inhibition effect on A549 and NCI-H460 cells using the MTT assay. Furthermore, treatment with GA significantly increased autophagy in these cells. More importantly, GA-induced cell death could be largely abolished by 3-methyladenine (3-MA) or chloroquine (CQ) treatment, suggesting that GA-induced cell death was dependent on autophagy. Western blot analysis showed that GA treatment suppressed the activation of Akt, mTOR, and S6. In addition, using a GA and rapamycin combination induced more cell death compared to either GA or rapamycin alone. In summary, GA may have utility as an adjunct therapy for non-small cell lung cancer (NSCLC) patients through autophagy-dependent cell death, even when cancer cells have developed resistance to apoptosis.

Topics: A549 Cells; Adenine; Antineoplastic Agents, Phytogenic; Autophagy; Cell Line, Tumor; Cell Proliferation; Chloroquine; Cisplatin; Drug Combinations; Drug Synergism; Garcinia; Gene Expression Regulation, Neoplastic; Humans; Microtubule-Associated Proteins; Plant Extracts; Proto-Oncogene Proteins c-akt; Ribosomal Protein S6; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Xanthones