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:3.4.22.B10 (
caspase-7
)
896
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Numerous solid tumors and hematologic malignancies acquire resistance to apoptosis-inducing chemotherapeutic drugs by downregulating the key effector caspase-3. These cells rely on
caspase-7
to execute the apoptotic program, yet binding with XIAP constitutively inhibits active
caspase-7
(
p19
/p12-CASP7). In this issue, Lin et al. describe how a newly synthesized drug is able to disrupt the XIAP:
p19
/p12-CASP7 complex and induce apoptosis in caspase-3-deficient cancer cells in vitro and in vivo. As this compound appears to exhibit minimal toxicity on normal tissues, it may represent a promising therapeutic agent to help treat caspase-3-deficient tumors.
...
PMID:Unshackling caspase-7 for cancer therapy. 2397 66
Caspase-3 downregulation (CASP3/DR) in tumors frequently confers resistance to cancer therapy and is significantly correlated with a poor prognosis in cancer patients. Because CASP3/DR cancer cells rely heavily on the activity of
caspase-7
(
CASP7
) to initiate apoptosis, inhibition of activated
CASP7
(
p19
/p12-
CASP7
) by X-linked inhibitor of apoptosis protein (XIAP) is a potential mechanism by which apoptosis is prevented in those cancer cells. Here, we identify the pocket surrounding the Cys246 residue of
p19
/p12-
CASP7
as a target for the development of a protein-protein interaction (PPI) inhibitor of the XIAP:
p19
/p12-
CASP7
complex. Interrupting this PPI directly triggered
CASP7
-dependent apoptotic signaling that bypassed the activation of the apical caspases and selectively killed CASP3/DR malignancies in vitro and in vivo without adverse side effects in nontumor cells. Importantly, CASP3/DR combined with
p19
/p12-
CASP7
accumulation correlated with the aggressive evolution of clinical malignancies and a poor prognosis in cancer patients. Moreover, targeting of this PPI effectively killed cancer cells with multidrug resistance due to microRNA let-7a-1-mediated CASP3/DR and resensitized cancer cells to chemotherapy-induced apoptosis. These findings not only provide an opportunity to treat CASP3/DR malignancies by targeting the XIAP:
p19
/p12-
CASP7
complex, but also elucidate the molecular mechanism underlying CASP3/DR in cancers.
...
PMID:Targeting the XIAP/caspase-7 complex selectively kills caspase-3-deficient malignancies. 2397 56
