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: EC:2.7.12.2 (
MEK
)
18,161
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Sangivamycin, a structural analog of adenosine and antibiotic exhibiting antitumor and antivirus activities, inhibits protein kinase C and the synthesis of both DNA and RNA.
Primary effusion lymphoma
(
PEL
) is an aggressive neoplasm caused by Kaposi's sarcoma-associated herpesvirus (KSHV) in immunosuppressed patients and HIV-infected homosexual males.
PEL
cells are derived from post-germinal center B cells, and are infected with KSHV. Herein, we asked if sangivamycin might be useful to treat
PEL
. We found that sangivamycin killed
PEL
cells, and we explored the underlying mechanism. Sangivamycin treatment drastically decreased the viability of
PEL
cell lines compared to KSHV-uninfected B lymphoma cell lines. Sangivamycin induced the apoptosis of
PEL
cells by activating caspase-7 and -9. Further, sangivamycin suppressed the phosphorylation of Erk1/2 and Akt, thus inhibiting activation of the proteins. Inhibitors of Akt and
MEK
suppressed the proliferation of
PEL
cells compared to KSHV-uninfected cells. It is known that activation of Erk and Akt signaling inhibits apoptosis and promotes proliferation in
PEL
cells. Our data therefore suggest that sangivamycin induces apoptosis by inhibiting Erk and Akt signaling in such cells. We next investigated whether sangivamycin, in combination with an HSP90 inhibitor geldanamycin (GA) or valproate (valproic acid), potentiated the cytotoxic effects of the latter drugs on
PEL
cells. Compared to treatment with GA or valproate alone, the addition of sangivamycin enhanced cytotoxic activity. Our data thus indicate that sangivamycin may find clinical utility as a novel anti-cancer agent targeting
PEL
.
...
PMID:Sangivamycin induces apoptosis by suppressing Erk signaling in primary effusion lymphoma cells. 2443 42
Primary effusion lymphoma
(
PEL
) is a lymphoma that shows malignant effusion in body cavities without contiguous tumor masses and has a very poor prognosis. We recently developed a novel drug screening system using patient-derived xenograft (PDX) cells that maintained the primary cell phenotype better than cell lines. This screening is expected to discover anti-tumor drugs that have been overlooked by conventional screening using cell lines. We herein performed this screening to identify new therapeutic agents for
PEL
. We screened 3518 compounds with known pharmaceutical activities based on cytotoxic effects on PDX cells of
PEL
and selected YM155, a possible survivin inhibitor. It exerted strong anti-tumor effects in PDX cells and three cell lines of
PEL
; the GI
50
of YM155 was 1.2-7.9nM. We found that YM155 reduced myeloid cell leukemia-1 (MCL-1) protein levels prior to decreasing survivin levels, and this was inhibited by a proteasome inhibitor. The knockdown of MCL-1 by siRNA induced cell death in a
PEL
cell line, suggesting the involvement of decreased MCL-1 levels in YM155-induced cell death. YM155 also induced the phosphorylation of ERK1/2 and MCL-1, and a
MEK1
inhibitor inhibited the phosphorylation of ERK1/2, degradation of MCL-1, and YM155-induced apoptosis. These results indicate that YM155 induces the proteasome-dependent degradation of MCL-1 through its phosphorylation by ERK1/2 and causes apoptosis in
PEL
cells. Furthermore, a treatment with YM155 significantly inhibited the development of ascites in
PEL
PDX mice. These results suggest the potential of YM155 as an anti-cancer agent for
PEL
.
...
PMID:YM155 induces apoptosis through proteasome-dependent degradation of MCL-1 in primary effusion lymphoma. 2839 94
