Small-molecule
drug combination therapies are an attractive approach to enhancing
cancer chemotherapeutic responses. Therefore, this study aimed to investigate the potential of
axitinib (AXT) and
celastrol (CST) in targeting angiogenesis and mitochondrial-based apoptosis in
cancer. Therefore, we prepared AXT/CST-loaded combination nanoparticles (ACML) with CST loaded in the mesoporous
silica nanoparticles (MSN) and AXT in PEGylated lipidic bilayers. We showed that ACML effectively inhibited angiogenesis and mitochondrial function and was efficiently internalized in SCC-7, BT-474, and SH-SY5Y cells. Furthermore,
hypoxia-inducible factor (HIF)-1α expression, which increased under hypoxic conditions in all cell lines exposed to ACML, markedly decreased, which may be critical for
tumor inhibition. Western blotting showed the superior anticancer effect of combination nanoparticles in different
cancer cells. Compared to the cocktail (AXT/CST), ACML induced synergistic
cancer cell apoptosis. The AXT/CST-based combination nanoparticle synergism might be mediated by AXT, which controls
vascular endothelial growth factor receptors while CST acts on target cell mitochondria. Importantly, ACML-treated mice showed remarkably higher
tumor inhibition (64%) than other groups did in
tumor xenograft models.
Tumor xenograft immunohistochemistry revealed elevated
caspase-3 and
poly (ADP-ribose) polymerase and reduced CD31 and Ki-67 expression, clearly suggesting
tumor apoptosis through mitochondrial and antiangiogenic effects. Overall, our results indicate that ACML potentially inhibited cell proliferation and induced apoptosis by blocking mitochondrial function, leading to enhanced antitumor efficacy.
STATEMENT OF SIGNIFICANCE: In this research, we formulated an
anticancer drug combination nanoparticle loaded with
axitinib (AXT) in the lipidic bilayer of PEGylated
liposomes and
celastrol (CST) in mesoporous
silica nanoparticles. The anticancer effects of the AXT/CST-loaded combination nanoparticle (ACML) were synergistic and superior to the other formulations and involved more efficient drug delivery to the
tumor site with enhanced effects on angiogenesis and mitochondrial function. Therefore, our study demonstrated that the inhibition of cell proliferation and induction of apoptosis by ACML, which was mediated by blockade of mitochondrial function and anti-angiogenesis, led to enhanced antitumor efficacy, which may be potentially useful in the clinical treatment of
cancer.