Background: Multi-drug resistance (MDR) remains a major impediment in cancer therapy. A major
goal for scientists is to discover more effective compounds that are able to circumvent MDR and simultaneously
have minimal adverse side effects.
Objective: In the present study, we aim to determine the anti-MDR effects of pyramidatine (Z88), a cinnamic
acid-derived bisamide compound isolated from the leaves of Aglaia perviridis, on KB/VCR (vincristineresistant
human oral cancer cells) and MCF-7/ADR (adriamycin-resistant human breast adenocarcinoma) cells.
Methods: Cell viability and average resistant fold (RF) of Z88 were examined by Cell Counting Kit-8 (CCK-8)
assay. Flow cytometry, western blot, RT-PCR, Rhodamine 123 accumulation assay and P-glycoprotein (P-gp)
ATPase assay were used to demonstrate the anti-MDR activity and mechanism of Z88.
Results: The average RF of Z88 is 0.09 and 0.51 in KB/VCR and MCF-7/ADR 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 Pgp
ATPase activity. Additionally, qPCR detection and western blot assays revealed that Z88 could decrease the
expression of P-gp at both RNA and protein level.
Conclusion: Z88 exerted potent anti-MDR activity in vitro and its mechanisms are associated with dualinhibition
of the function and expression of P-gp. These findings encourage efforts to develop more effective
reversal agents to circumvent MDR based on Z88.