Abstract
Triple-negative breast cancers (TNBCs)
comprise 10–15% of
all breast cancers but with more resistance affinity against chemotherapeutics.
Although doxorubicin (DOX) is the recommended first choice, it has
observed cardiotoxicity together with apparent drug resistance. The
anti-hyperglycemic drug, empagliflozin (EMP), was recently indicated
to have
in vitro
anticancer potential together with
its previously reported cardioprotective properties related to calmodulin
inhibition. In this study, we carried out molecular docking studies
which revealed the potential blocking of the calmodulin receptor by
EMP through its binding with similar crucial amino acids compared
to its cocrystallized inhibitor (AAA) as a proposed mechanism of action.
Moreover, combination of DOX with EMP showed a slightly lower cytotoxic
activity against the MDA-MB-231 cell line (IC
50
= 1.700
± 0.121) compared to DOX alone (IC
50
= 1.230 ±
0.131), but it achieved a more characteristic arrest in the growth
of cells by 4.67-fold more than DOX alone (with only 3.27-fold) in
comparison to the control as determined by cell cycle analysis, and
at the same time reached an increase in the total apoptosis percentage
from 27.05- to 29.22-fold, compared to DOX alone as indicated by Annexin
V-FITC apoptosis assay. Briefly, the aforementioned
in vitro
studies in addition to PCR of pro- and antiapoptotic genes (mTOR,
p21, JNK, Bcl2, and MDR1) suggest the chemosensitization effect of
EMP combination with DOX which can reduce the required therapeutic
dose of DOX in TNBC and eventually will decrease its toxic side effects
(especially cardiotoxicity), along with decreasing the chemoresistance
of TNBC cells to DOX treatment.