Abstract
Matrine and arsenic trioxide are monomers used in traditional Chinese
medicine possessing anti-myeloma activities. In this study, we evaluated the
effects and mechanisms of matrine, arsenic trioxide, and their combination
therapy on the proliferation and apoptosis of the myeloma cell lines
RPMI8226 and U266. The effects of growth inhibition were measured by MTT,
and apoptotic cells were analyzed by Hoechst 33258 staining and flow
cytometry. The levels of caspase-3, poly (ADP-ribose) polymerase (a DNA
repair enzyme), Bcl-2 and survivin (antiapoptotic signaling proteins), Bim
(a proapoptotic signaling protein), total AKT, and phosphorylated AKT were
evaluated by Western blot. Matrine significantly inhibited proliferation of
RPMI8226 and U266 cell lines in a dose- and time-dependent manner with an
IC50 at 24 h of 2.25 g/L and 2.18 g/L, and at 48 h of
1.64 g/L and 1.58 g/L, respectively. Arsenic trioxide also displayed a dose-
and time-dependent inhibition of growth of multiple myeloma cell lines, and
synergistic effects occurred when the two were combined. Matrine (0.5,
1.0 g/L) and arsenic trioxide (2, 4 ug/mL) induced the apoptosis of myeloma
cells; more early-stage apoptotic cells were seen with the combination
therapy (matrine 0.5 g/L plus arsenic trioxide 2 ug/mL and matrine 1.0 g/L
plus arsenic trioxide 4 ug/mL). Activation of caspase-3 and poly
(ADP-ribose) polymerase, upregulation of Bim expression, downregulation of
Bcl-2, survivin expression, as well as inhibition of phosphorylated AKT
related to matrine (0, 0.25, 0.5, 1.0, and 2.0 g/L)-mediated apoptosis, and
the effects were enhanced when arsenic trioxide (8 ug/mL) was combined with
matrine (1.0 g/L). In conclusion, matrine displayed anti-myeloma effects
through apoptotic induction, and arsenic trioxide had synergistic effects
with matrine enhancing matrine-induced apoptosis.
Key words
matrine - arsenic trioxide - multiple myeloma - apoptosis
