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:C0079731 (
B-cell lymphoma
)
16,671
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
BH3 mimetics are small-molecule inhibitors of
B-cell lymphoma
-2 (Bcl-2) and Bcl-xL, which disrupt the heterodimerisation of anti- and pro-apoptotic Bcl-2 family members sensitising cells to apoptotic death. These compounds have been developed as anti-cancer agents to counteract increased levels of Bcl-2 proteins often present in cancer cells. Application of a chemotherapeutic drug supported with a BH3 mimetic has the potential to overcome drug resistance in cancers overexpressing anti-apoptotic Bcl-2 proteins and thus increase the success rate of the treatment. We have previously shown that the BH3 mimetics, BH3I-2' and HA14-1, induce Ca
2+
release from intracellular stores followed by a sustained elevation of the cytosolic Ca
2+
concentration. Here we demonstrate that loss of Bax, but not Bcl-2 or Bak, inhibits this sustained Ca
2+
elevation. What is more, in the absence of Bax, thapsigargin-elicited responses were decreased; and in two-photon-permeabilised bax
-/-
cells, Ca
2+
loss from the ER was reduced compared to WT cells. The Ca
2+
-like peptides,
CALP
-1 and
CALP
-3, which activate EF hand motifs of Ca
2+
-binding proteins, significantly reduced excessive Ca
2+
signals and necrosis caused by two BH3 mimetics: BH3I-2' and gossypol. In the presence of
CALP
-1, cell death was shifted from necrotic towards apoptotic, whereas
CALP
-3 increased the proportion of live cells. Importantly, neither of the CALPs markedly affected physiological Ca
2+
signals elicited by ACh, or cholecystokinin. In conclusion, the reduction in passive ER Ca
2+
leak in bax
-/-
cells as well as the fact that BH3 mimetics trigger substantial Ca
2+
signals by liberating Bax, indicate that Bax may regulate Ca
2+
leak channels in the ER. This study also demonstrates proof-of-principle that pre-activation of EF hand Ca
2+
-binding sites by CALPs can be used to ameliorate excessive Ca
2+
signals caused by BH3 mimetics and shift necrotic death towards apoptosis.
...
PMID:BH3 mimetic-elicited Ca
2+
signals in pancreatic acinar cells are dependent on Bax and can be reduced by Ca
2+
-like peptides. 2825 52
