Treatment of acute promyelocytic leukemia with ATRA and As2O3: a model of molecular target-based cancer therapy.
Most acute promyelocytic leukemia (APL) cases have t(15;17)(q22;q21) chromosomal translocation and PML-RARalpha chimeric gene which blocks granulocytic differentiation. The introduction of all-trans-retinoic acid (ATRA) and arsenic compounds, especially arsenic trioxide (As(2)O(3)), has provided good models to study not only differentiation and/or apoptosis therapy but also molecular target-based cancer treatment. In vivo and in vitro investigations have shown that both agents are able to induce differentiation of APL cells: ATRA tends to induce terminal differentiation, while low-dose As(2)O(3) can induce partial differentiation. Significant progress has been made in understanding the molecular mechanisms of APL pathogenesis and differentiation therapy. Pharmacological concentrations (0.1 approximately 1 microM) of ATRA derepresses transcription by releasing CoR from, and recruiting CoA to PML-RARalpha, whereas As(2)O(3) triggers a rapid degradation of PML-RARalpha. In fact, the two drugs act on the same oncoprotein through targeting different moieties and in distinct ways and thereby abrogate its dominant-negative effects on regulatory pathways necessary for granulocytic differentiation. As to apoptosis, it is clear that high-dose As(2)O(3) can induce mitochondria-mediated cell death pathway in a thiol-dependent manner, while the mechanism of ATRA-induced apoptosis needs further elucidation. Transcriptomic and proteomic analysis are also expected to find new molecular targets. It is the hope that what we have learnt from APL will benefit further developments of anti-leukemia therapy.
Fang
Jing
J
State Key Lab of Medical Genomics, Shanghai Institute of Hematology, Ruijin Hospital affiliated to Shanghai Second Medical University, Shanghai, P. R. China.
Chen
Sai-Juan
SJ
Tong
Jian-Hua
JH
Wang
Zhu-Gang
ZG
Chen
Guo-Qiang
GQ
Chen
Zhu
Z
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000627:therapeutic use*; D002454:Cell Differentiation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy* / Q000473:pathology; D009363:Neoplasm Proteins / Q000187:drug effects; D015514:Oncogene Proteins, Fusion / Q000187:drug effects; D010087:Oxides / Q000627:therapeutic use*; D014178:Translocation, Genetic / Q000235:genetics; D014212:Tretinoin / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D001152:Arsenicals; D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; D010087:Oxides; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; D014212:Tretinoin; D000077237:Arsenic Trioxide