Pyramidatine (Z88) Sensitizes Vincristine-Resistant Human Oral Cancer (KB/VCR) Cells to Chemotherapeutic Agents by Inhibition of P- glycoprotein.

Multi-drug resistance (MDR) to anticancer drugs remains a major impediment in cancer therapy. A major goal for scientists is to identify more effective compounds that are able to circumvent MDR and simultaneously have minimal adverse side effects. Here, we reported that Pyramidatine (Z88), a cinnamic acid-derived bisamide compound isolated from the leaves of Aglaia perviridis, had potent anti-MDR activity. The average resistant fold (RF) of Z88 is 0.09 and 0.51 in KB/VCR (vincristine-resistant human oral cancer cells) and MCF-7/ADR (adriamycin-resistant human breast adenocarcinoma) cells. A CCK-8 assay showed that Z88 could enhance the cytotoxicity of VCR toward KB/VCR cells. A FACS analysis revealed that Z88 could enhance the VCR-induced apoptosis as well as G2/M arrest in a dose-dependent manner in KB/VCR cells. Western Blot results showed that the expression levels of PARP, Bax, and Cyclin B1 all increased after treatment with 0.2 μmol/L (μM) of VCR combined with 10 μM of Z88 for 24 h in KB/VCR cells. Z88 also could enhance the accumulation of rhodamine 123. Further studies showed that Z88 could inhibit the verapamil-stimulated P- glycoprotein (P-gp) ATPase activity. Additionally, qPCR detection and western blot assays revealed that Z88 could decrease the RNA transcript level of ABCB1 and the protein expression level of P-gp. In conclusion, Z88 exerted potent anti-MDR activity in vitro and its mechanisms may be associated with dual-inhibition of the function and expression of P-gp. These findings encourage efforts todevelop more effective reversal agents to circumvent MDR.