Therapeutic metformin/AMPK activation blocked lymphoma cell growth via inhibition of mTOR pathway and induction of autophagy.

摘要: Adenosine monophosphate-activated protein kinase (AMPK) acts as a major sensor of cellular energy status in cancers and is critically involved cell sensitivity to anticancer agents. Here, we showed that AMPK was inactivated lymphoma related the upregulation mammalian target rapamycin (mTOR) pathway. activator metformin potentially inhibited growth B- T-lymphoma cells. Strong antitumor effect also observed on primary cells while sparing normal hematopoiesis ex vivo. Metformin-induced activation associated with inhibition mTOR signaling without involving AKT. Moreover, response chemotherapeutic agent doxorubicin inhibitor temsirolimus significantly enhanced when co-treated metformin. Pharmacologic molecular knock-down attenuated metformin-mediated drug sensitization. In vivo, induced activation, remarkably blocked tumor murine xenografts. Of note, equally effective given orally. Combined treatment oral or triggered autophagy functioned more efficiently than either alone. Taken together, these data provided first evidence for growth-inhibitory drug-sensitizing lymphoma. Selectively targeting pathway through may thus represent promising new strategy improve patients.