Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: UMLS:C0677930 (
primary tumor
)
20,210
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Malignant mesothelioma (MM) is a
primary tumor
arising from mesothelial cells. The survival of MM patients following traditional chemotherapy is poor, thus innovative treatments for MM are needed. (-)-gossypol (
AT-101
) is a BH3 mimetic compound which possesses anti-tumoral activity by targeting multiple signaling transduction pathways. Several clinical trials employing
AT-101
have been performed and some of them are still ongoing. Accordingly, we investigated the
in vitro
effects of
AT-101
on cell proliferation, cell cycle regulation, pro-survival signaling pathways, apoptosis and autophagy of human (MM-B1, H-Meso-1, and MM-F1) and mouse (#40a) MM cell lines. In addition, we explored the
in vivo
anti-tumor activities of
AT-101
in a mouse model, in which the transplantation of MM cells induces ascites in the peritoneal space.
AT-101
inhibited
in vitro
MM cells survival in a dose- and time-dependent manner and triggered autophagy, but the process was then blocked and was coincident with apoptosis activation. To confirm the effect of
AT-101
in inducing the apoptosis of MM cells, MM cells were simultaneously treated with
AT-101
and with the caspase inhibitor, Z-VAD-FMK. Z-VAD-FMK was able to significantly reduce the number of cells in the subG1 phase compared to the treatment with
AT-101
alone. This result corroborates the induction of cell death by apoptosis following treatment with
AT-101
. Indeed, Western blotting results showed that
AT-101
increases Bax/Bcl-2 ratio, modulates p53 expression, activates caspase 9 and the cleavage of PARP-1. In addition, the treatment with
AT-101
was able to: (a) decrease the ErbB2 protein expression; (b) increase the EGFR protein expression; (c) affect the phosphorylation of ERK1/2, p38 and AKT; (d) stimulate JNK1/2 and c-jun phosphorylation. Our
in vivo
results showed that the intraperitoneal administration of
AT-101
increased the median survival of
C57BL/6
mice intraperitoneally transplanted with #40a cells and reduced the risk of developing tumors. Our findings may have important implications for the design of MM therapies by employing
AT-101
as an anticancer agent in combination with standard therapies.
...
PMID:Effect of the BH3 Mimetic Polyphenol (-)-Gossypol (AT-101) on the
in vitro
and
in vivo
Growth of Malignant Mesothelioma. 3045 22
