Rapamycin provides a therapeutic option through inhibition of mTOR signaling in chronic myelogenous leukemia

Abstract

Abstract. Chronic myelogenous leukemia (CML) is a neoplasm of myeloid progenitor cells expressing Bcr-Abl fusion protein.However, some patients with CML are less likely to respond to imatinib, the inhibitor of Bcr-Abl kinase. Recent studies showed that mTOR pathway can increase responses to imatinib. The analysis of mTOR pathway in CML may provide new insights into possible targets of novel therapies. Therefore, we examined the expression of mTOR pathway molecules in bone marrow cells from CML patients and effect of rapamycin on K562 cells in vitro. Western blot analysis showed the visibly higher phosphorylation of mTOR (70.6%), 4E-BP1 (76.5%) and p70S6K (73.5%) in bone marrow cells from CML patients. Moreover, treatment of CML cell line (K562) with rapamycin resulted in a decrease of phosphorylation of mTOR, 4E-BP1 and p70S6K. In vitro, the cell viability in groups with rapamycin treatment displayed a significant decrease in a dose-dependent manner by MTT. The data presented an increase of G 0 /G 1 phase cells and decrease of S phase cells after rapamycin treatment, and the decreased expression of cyclinD1, higher expression of p21 at mRNA level was also detected in K562 with rapamycin. Treatment with 20 nmol/l or more rapamycin could increase apoptotic cells, decrease expression of bcl-2 and activate caspase-3. In conclusion, the mTOR pathway might be involved in chronic myelogenous leukemia. Inhibition of mTOR pathway could interfer with cell proliferation and increase cell apoptosis in K562 cells. It suggested that mTOR might be an important therapeutic target for myelogenous leukemia.

PI3K/mTOR pathway inhibitors sensitize chronic myeloid leukemia stem cells to nilotinib and restore the response of progenitors to nilotinib in the presence of stem cell factor

“…It has recently been shown that the rapamycin-induced mTOR inhibition decreased the proliferation of K562 cell lines. 25 Moreover, clinical and preclinical studies have demonstrated that mTORC1 inhibitors synergized with imatinib to increase apoptosis in CML cells 26 , 27 and restored the sensitivity to imatinib-resistant cells. 14 …”

Rapamycin enhanced the antitumor effects of doxorubicin in myelogenous leukemia K562 cells by downregulating the mTOR/p70S6K pathway

“…In addition, the mTOR pathway has been found to be activated in leukemia cells, especially in cell lines expressing Bcr/Abl (8–11). Previous studies demonstrated that the mTOR pathway was activated in myeloid leukemia, including CML, and mTOR inhibitor (rapamycin, sapanisertib) could arrest cells at the G 0 /G 1 phase and increase apoptosis in leukemia cells (12–14). mTOR is a serine/threonine kinase which plays important roles in the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/Protein Kinase B (AKT)/mTOR pathway.…”

“…This is important for mitogen-induced cell proliferation and chemotherapeutic drug resistance in cancer cells (21,22). The authors' previous study showed that p70S6K and 4E-BP1 were overexpressed and phosphorylated in CML bone marrow and K562 cells (12). It was therefore speculated that rapamycin could enhance the antitumor effects of chemotherapy on leukemia cells through downregulating mTOR signaling.…”

mTOR ATP-competitive inhibitor INK128 inhibits neuroblastoma growth via blocking mTORC signaling

“…mTOR exists as two functional multi-protein complexes, mTORC1 and mTORC2. Previous studies suggest that inhibition of mTOR phosphorylation by mTOR inhibitors results in inhibition of cell growth, G0/G1 phase arrest, and induction of apoptosis [5–7]. However, the traditional mTOR inhibitors rapamycin and rapalogs, either used as single agent or in combination with other drugs, only have modest clinical activity against various tumors.…”