Activation of adenylate cyclase influences the sensitivity of acute promyelocytic leukemia cell lines to ATRA.
- Author:
Ai-xia DOU
1
;
Pei-min JIA
;
Qi ZHU
;
Qian ZHAO
;
Zhen-yi WANG
;
Jian-hua TONG
Author Information
- Publication Type:Journal Article
- MeSH: Adenine; analogs & derivatives; pharmacology; Adenylyl Cyclase Inhibitors; Adenylyl Cyclases; metabolism; Antineoplastic Agents; pharmacology; CD11b Antigen; metabolism; Cell Differentiation; drug effects; Cell Line, Tumor; Drug Resistance, Neoplasm; drug effects; Enzyme Activation; drug effects; Enzyme Inhibitors; pharmacology; Humans; Leukemia, Promyelocytic, Acute; metabolism; pathology; Phosphoric Diester Hydrolases; metabolism; Tretinoin; pharmacology
- From: Chinese Journal of Hematology 2004;25(11):675-678
- CountryChina
- Language:Chinese
-
Abstract:
OBJECTIVETo explore the molecular mechanism of APL cell resistance to ATRA.
METHODSThe ATRA sensitive and resistant APL cell lines, NB4 and NB4-R1, were used as in vitro models. The effects of specific inhibitors and activators of adenylate cyclase (AC) and phosphodiesterase (PDE) on ATRA-induced differentiation was evaluated by cell morphology, cell surface antigen expression and nitroblue-tetrazolium (NBT) reduction assays.
RESULTSSQ22536, a specific antagonist of AC, could dramatically block ATRA-induced NB4 cell differentiation. When ATRA + SQ22536 group compared with ATRA group, the positivity of CD11b decreased from (95.9 +/- 2.5)% to (60.3 +/- 7.1)%, while the A(540) in NBT reduction assay decreased from 0.585 +/- 0.092 to 0.170 +/- 0.028 (P < 0.05). Forskolin, an agonist of AC, could overcome the resistance of NB4-R1 cells to ATRA. When ATRA + forskolin group compared with ATRA group, the positivity of CD11b increased from (34.3 +/- 5.3)% to (94.6 +/- 2.4)%, while the A(540) in NBT reduction assay increased from 0.110 +/- 0.028 to 0.395 +/- 0.049 (P < 0.05). In contrast, the specific antagonist and agonist of PDE, 3-isobutyl-1-methylxanthine (IBMX) and calmodulin, exerted little impact on ATRA treatment.
CONCLUSIONSThe defaults in the initiation of AC activation may contribute to the resistance to ATRA in some APL cells.
