Pharicin B stabilizes retinoic acid receptor-α and presents synergistic differentiation induction with ATRA in myeloid leukemic cells.
All-trans retinoic acid (ATRA), a natural ligand for the retinoic acid receptors (RARs), induces clinical remission in most acute promyelocytic leukemia (APL) patients through the induction of differentiation and/or eradication of leukemia-initiating cells. Here, we identify a novel natural ent-kaurene diterpenoid derived from Isodon pharicus leaves, called pharicin B, that can rapidly stabilize RAR-α protein in various acute myeloid leukemic (AML) cell lines and primary leukemic cells from AML patients, even in the presence of ATRA, which is known to induce the loss of RAR-α protein. Pharicin B also enhances ATRA-dependent the transcriptional activity of RAR-α protein in the promyelocytic leukemia-RARα-positive APL cell line NB4 cells. We also showed that pharicin B presents a synergistic or additive differentiation-enhancing effect when used in combination with ATRA in several AML cell lines and, especially, some primary leukemic cells from APL patients. In addition, pharicin B can overcome retinoid resistance in 2 of 3 NB4-derived ATRA-resistant subclones. These findings provide a good example for chemical biology-based investigations of pathophysiological and therapeutic significances of RAR-α and PML-RAR-α proteins. The effectiveness of the ATRA/pharicin B combination warrants further investigation on their use as a therapeutic strategy for AML patients.
Gu
Zhi-Min
ZM
Institute of Health Sciences, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS) and Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai, China.
Wu
Ying-Li
YL
Zhou
Mei-Yi
MY
Liu
Chuan-Xu
CX
Xu
Han-Zhang
HZ
Yan
Hua
H
Zhao
Yong
Y
Huang
Ying
Y
Sun
Han-Dong
HD
Chen
Guo-Qiang
GQ
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects*; D045744:Cell Line, Tumor; D045786:Diterpenes, Kaurane / Q000494:pharmacology* / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D006801:Humans; D037602:Isodon / Q000737:chemistry; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000473:pathology; D055550:Protein Stability / Q000187:drug effects; D018168:Receptors, Retinoic Acid / Q000737:chemistry*; D000072482:Retinoic Acid Receptor alpha; D015533:Transcriptional Activation / Q000187:drug effects; D014212:Tretinoin / Q000494:pharmacology* / Q000627:therapeutic use; D014407:Tumor Cells, Cultured
D045786:Diterpenes, Kaurane; C000607071:RARA protein, human; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; C554739:pharicin B; D014212:Tretinoin