Gambogic acid (GA) is known for its anti-cancer activity in a phase II clinical trial. However, the detailed molecular mechanisms of its anti-multidrug resistance remain unclear. The present study was designed to study the relationship between GA and multidrug-resistant protein ATP-binding cassette transporter B1 (ABCB1). GA dose dependently inhibited ABCB1 activity levels in the in vitro Pgp-Glo assay system and increased the cellular accumulation of ABCB1 substrate adriamycin. Although GA had no significant influence on ABCB1 mRNA in the real-time PCR assay, Western blot detection indicated the compound reduced ABCB1 protein levels. Further study showed the proteasome inhibitor MG-132 reversed the GA-decreased ABCB1 level and prolonged half-life of ABCB1. It was also found that GA coordinated with other anti-cancer drugs (such as adriamycin, docetaxel, verapamil and protopanaxadiol) to enhance cellular cytotoxicity on human epithelial cancer cell lines with higher ABCB1 expression levels. These data suggest that GA functions as a non-competitive inhibitor of ABCB1 by directly inhibiting and reducing its expression levels by promoting protein degradation through post-translational proteasome pathway. The results of this study will aid in the understanding of the synergistic effects of combining GA with other drugs as a new anti-multidrug-resistant agent.

Novel 20(S)-protopanoxadiol (PPD) analogues were designed, synthesized, and evaluated for the chemosensitizing activity against a multidrug resistant (MDR) cell line (KBvcr) overexpressing P-glycoprotein (P-gp). Structure-activity relationship analysis showed that aromatic substituted aliphatic amine at the 24-positions (groups V) effectively and significantly sensitized P-gp overexpressing multidrug resistant (MDR) cells to anticancer drugs, such as docetaxel (DOC), vincristine (VCR), and adriamycin (ADM). PPD derivatives 12 and 18 showed 1.3-2.6 times more effective reversal ability than verapamil (VER) for DOC and VCR. Importantly, no cytotoxicity was observed by the active PPD analogues (5μM) against both non-MDR and MDR cells, suggesting that PPD analogues serve as novel lead compounds toward a potent and safe resistance modulator. Moreover, a preliminary mechanism study demonstrated that the chemosensitizing activity of PPD analogues results from inhibition of P-glycoprotein (P-gp) overexpressed in MDR cancer cells.

Background: The purpose of this study was to elucidate the clinicopathological characteristics of patients with lymphoepithelial carcinoma of salivary gland (LEC-SG) and determine the factors associated with survival.Methods: A total of 179 LEC-SG patients from the Surveillance, Epidemiology, and End Results (SEER) database between 1975 to 2016 were included. The clinicopathological characteristics and overall survival of LEC-SG patients were described, and the features affecting prognosis were further determined using Kaplan-Meier Curves and Cox survival analysis. Results:The median overall survival of LEC-SG patients was 206 months, and the 1-, 5-, 10-and 20-year survival rates were 91.0%, 80.2%, 66.4%, and 37.6%, respectively. The prognoses were significantly associated with age, ethnicity, marital status, tumor invasion, as well as lymph node metastases [P<0.01 for all). Surgical resection could significantly improve the prognosis of this disease (median overall survival (mOS): 219 vs. 68 months, P<0.01]. Postoperative radiotherapy could improve long-term survival and decrease the risk of death among patients who survive exceed 10-year after surgery. The Cox regression analysis showed that old age (>60 years) and lymph node metastases were independently associated with poor survival (P<0.05 for both). Conversely, the use of surgery was an independent favorable prognostic factor [hazard ratio (HR) 0.29, 95% CI: 0.13-0.66].Conclusions: LEC-SG patients had a favorable prognosis with a mOS of 206 months. Old age, lymph node metastases, the use of surgery were independently associated with survival of LEC-SG patients.