Small molecule inhibition of Dynamin-dependent endocytosis targets multiple niche signals and impairs leukemia stem cells

Abstract

Intensive chemotherapy for acute leukemia can usually induce complete remission, but fails in many patients to eradicate the leukemia stem cells responsible for relapse. There is accumulating evidence that these relapse-inducing cells are maintained and protected by signals provided by the microenvironment. Thus, inhibition of niche signals is a proposed strategy to target leukemia stem cells but this requires knowledge of the critical signals and may be subject to compensatory mechanisms. Signals from the niche require receptor-mediated endocytosis, a generic process dependent on the Dynamin family of large GTPases. Here, we show that Dynole 34-2, a potent inhibitor of Dynamin GTPase activity, can block transduction of key signalling pathways and overcome chemoresistance of leukemia stem cells. Our results provide a significant conceptual advance in therapeutic strategies for acute leukemia that may be applicable to other malignancies in which signals from the niche are involved in disease progression and chemoresistance.

Dynamin inhibition causes context-dependent cell death of leukemia and lymphoma cells

“…This points to the involvement of also other endocytosis-related, or non-related, mechanisms in the induction of the cell death response. In line with this, it has recently been suggested that dynamin inhibition blocks ligand-bound receptor internalization in leukemia cells, leading to apoptosis [ 16 ].…”

“…Hence, we favor the notion that dynamin inhibition preferentially impacts on proliferating cells. Notably though, previous investigations have suggested that dynamin inhibition can have an impact on cells with both low and high proliferative capacity [ 16 ]. Nevertheless, we here provide data on the effect of dynamin inhibition on non-adherent cancer cells, which complements previous studies where the focus has predominantly been on adherent cell lines [ 12 , 13 , 24 , 31 ].…”

“…One potential chemotherapeutic strategy in leukemia would be to inhibit dynamin, a key component of the machinery for clathrin-mediated endocytosis and also for cytokinesis [ 9 – 11 ]. Indeed, this strategy has been evaluated previously, but only to a limited extent in leukemia and other cell types [ 12 – 16 ]. The most well-studied inhibitor of dynamin is Dynasore, which inhibits the GTP-hydrolase activity of dynamin [ 17 ].…”

A review of Dynamin 2 involvement in cancers highlights a promising therapeutic target

“…In a prostate cancer mouse model in which formation of subcutaneous tumors are induced after injection of human prostatic adenocarcinoma cells, intratumoral injection of a DNM2 inhibitor (N'- [4-(dipropylamino) benzylidene]-2-hydroxybenzohydrazide, DBHA) rapidly reduces tumor size without apparent adverse effect [89]. In the same line, continuous delivery of the CyDyn4-36 DNM2 inhibitor by subcutaneous osmotic pumps reduces the size of established tumors formed by prior intracranial injection of glioma stem cells [82] and intraperitoneal injection of the Dynole 34.2 DNM2 inhibitor leads to progressive exhaustion of pre-leukemia stem cells in a mouse model of acute leukemia [90]. Dynole 34.2 also reduces the number of leukemic cells in the bone marrow and spleen of mice after T-ALL and acute myeloid leukemia cells xenografts [90].…”

“…In the same line, continuous delivery of the CyDyn4-36 DNM2 inhibitor by subcutaneous osmotic pumps reduces the size of established tumors formed by prior intracranial injection of glioma stem cells [82] and intraperitoneal injection of the Dynole 34.2 DNM2 inhibitor leads to progressive exhaustion of pre-leukemia stem cells in a mouse model of acute leukemia [90]. Dynole 34.2 also reduces the number of leukemic cells in the bone marrow and spleen of mice after T-ALL and acute myeloid leukemia cells xenografts [90]. DBHA, Dynole 34.2 and CyDyn4-36 represent a new generation of DNM2 inhibitors opening the way for future clinical use.…”