Targeting the liver kinase B1/AMP-activated protein kinase pathway as a therapeutic strategy for hematological malignancies.
BACKGROUND
Despite considerable advances, several hematological malignancies remain incurable with standard treatments. Therefore, there is a need for novel targeted and less toxic therapies, particularly for patients who develop resistance to traditional chemotherapeutic drugs. The liver kinase B1 (LKB1)/AMP-activated protein kinase (AMPK) signaling pathway has recently emerged as a tumor suppressor axis. A critical point is that the LKB1/AMPK network remains functional in a wide range of cancers and could be stimulated by drugs, such as N,N-dimethylimidodicarbonimidic diamide (metformin) or 5-aminoimidazole-4-carboxamide 1-β-D-ribofuranoside (AICAR).


METHODS
The literature data show that drugs activating LKB1/AMPK signaling induced cell cycle arrest, caspase-dependent apoptosis or autophagy in hematopoietic tumors. Moreover, metformin effectively inhibited mammalian target of rapamycin complex 1 (mTORC1)-controlled oncogenetic protein translation, which does not occur with allosteric mTORC1 inhibitors, such as rapamycin and its derivatives. Metformin was also capable of targeting leukemic stem cells, the most relevant target for leukemia eradication.


CONCLUSIONS
Data emerging from preclinical settings suggest that the LKB1/AMPK pathway is critically involved in regulating proliferation and survival of malignant hematopoietic cells. Thus, it is proposed that drugs activating the LKB1/AMPK axis may offer a novel and less toxic treatment option for some types of hematological malignancies.
University of Bologna, Human Anatomy, via Irnerio 48, Bologna, 40126, Italy. alberto.martelli@unibo.it
Alberto M
AM
Martelli
Francesca
F
Chiarini
Camilla
C
Evangelisti
Andrea
A
Ognibene
Daniela
D
Bressanin
Anna Maria
AM
Billi
Lucia
L
Manzoli
Alessandra
A
Cappellini
James A
JA
McCubrey
D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D019337:Hematologic Neoplasms / Q000188:drug therapy / Q000201:enzymology*; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases
D046912:Multiprotein Complexes; D011506:Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D058570:TOR Serine-Threonine Kinases; D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases