PMID- 26490657 OWN - NLM STAT- MEDLINE DCOM- 20160912 LR - 20211203 IS - 1573-0646 (Electronic) IS - 0167-6997 (Print) IS - 0167-6997 (Linking) VI - 33 IP - 6 DP - 2015 Dec TI - Effects of mTOR inhibitors and cytoskeletal-directed agents alone and in combination against normal and neoplastic hematopoietic cells in vitro. PG - 1162-74 LID - 10.1007/s10637-015-0294-7 [doi] AB - The mechanistic target of rapamycin (mTOR) controls cell growth and enlargement and has been found to be aberrant in a wide variety of malignancies. Although mTOR is already an attractive antineoplastic target, overexpression or aberrant expression of mTOR may also provide an opportunity to further increase the size differential between malignant and normal cells, providing an opportunity to amplify and exploit cell size differences between neoplastic cells and their normal counterparts using physiochemical treatment modalities. Therefore, this study sought to quantify the concentration response and time course effects of rapamycin on cell cycle entry, cell enlargement, and cell proliferation in U937 human monocytic leukemia and human hematopoietic stem cells (hHSCs). In addition, the effects of combination treatment with mTOR inhibitors (rapamycin, everolimus, and temsirolimus) and cytoskeletal-directed agents (cytochalasin B and vincristine) in leukemic cells (U937, THP1, K562, Molt-4, and L1210) were assessed for potential drug synergy. While both U937 cells and hHSCs exhibited a marked reduction in cell volume, U937 cells were able to proliferate in the presence of rapamycin ranging from 0.5 nM to 10 muM (10,000 nM), whereas hHSCs were able to proliferate only at lower concentrations, and were completely inhibited from proliferation by 8 nM rapamycin. These effects were observed with as little as 0.5 nM rapamycin, demonstrating the profound affinity the compound has for FK-binding protein 12 (FKBP12), which subsequently forms the FKBP12/rapamycin complex to inhibit mTOR. Rapamycin continued to exert effects on cell size and proliferation even at 10 muM, without producing marked cytotoxicity. Although cytochalasin B and vincristine were unable to substantially enlarge rapamycin-treated leukemia cells, it appears that rapamycin and its associated analogs everolimus and temsirolimus have notable synergistic potential with microfilament-disrupting cytochalasin B and microtubule-disrupting vincristine as assessed by comparative effects on cell growth, annexin V staining, IC30 isobolograms, and Chou-Talalay statistics. These observations indicate a potentially novel therapeutic rationale for hematological malignancies and for other cancers to elicit the preferential destruction of neoplastic cells that aberrantly express mTOR. FAU - Trendowski, Matthew AU - Trendowski M AD - Department of Biology, Syracuse University, 107 College Place, Syracuse, NY, 13244, USA. mrtrendo@syr.edu. FAU - Christen, Timothy D AU - Christen TD AD - Department of Biology, Syracuse University, 107 College Place, Syracuse, NY, 13244, USA. FAU - Andonova, Antoaneta A AU - Andonova AA AD - Department of Biology, Syracuse University, 107 College Place, Syracuse, NY, 13244, USA. FAU - Narampanawe, Berlini AU - Narampanawe B AD - Department of Biology, Syracuse University, 107 College Place, Syracuse, NY, 13244, USA. FAU - Thibaud, Ashlee AU - Thibaud A AD - Department of Biology, Syracuse University, 107 College Place, Syracuse, NY, 13244, USA. FAU - Kusang, Tenzin AU - Kusang T AD - Department of Biology, Syracuse University, 107 College Place, Syracuse, NY, 13244, USA. FAU - Fondy, Thomas P AU - Fondy TP AD - Department of Biology, Syracuse University, 107 College Place, Syracuse, NY, 13244, USA. LA - eng PT - Journal Article DEP - 20151022 PL - United States TA - Invest New Drugs JT - Investigational new drugs JID - 8309330 RN - 0 (Antibiotics, Antineoplastic) RN - EC 2.7.1.1 (MTOR protein, human) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - W36ZG6FT64 (Sirolimus) SB - IM MH - Antibiotics, Antineoplastic/*administration & dosage MH - Cell Line, Tumor MH - Cell Proliferation/drug effects/physiology MH - Cell Size MH - Cytoskeleton/*drug effects/metabolism MH - Dose-Response Relationship, Drug MH - *Hematologic Neoplasms/drug therapy/metabolism MH - Hematopoietic Stem Cells/*drug effects/metabolism MH - Humans MH - Sirolimus/*administration & dosage MH - TOR Serine-Threonine Kinases/*antagonists & inhibitors MH - U937 Cells PMC - PMC4648964 OTO - NOTNLM OT - Cytoskeletal-directed agents OT - Drug synergy OT - Hematopoietic stem cells OT - Leukemia OT - MTOR inhibitors EDAT- 2015/10/23 06:00 MHDA- 2016/09/13 06:00 PMCR- 2015/10/22 CRDT- 2015/10/23 06:00 PHST- 2015/08/30 00:00 [received] PHST- 2015/10/07 00:00 [accepted] PHST- 2015/10/23 06:00 [entrez] PHST- 2015/10/23 06:00 [pubmed] PHST- 2016/09/13 06:00 [medline] PHST- 2015/10/22 00:00 [pmc-release] AID - 10.1007/s10637-015-0294-7 [pii] AID - 294 [pii] AID - 10.1007/s10637-015-0294-7 [doi] PST - ppublish SO - Invest New Drugs. 2015 Dec;33(6):1162-74. doi: 10.1007/s10637-015-0294-7. Epub 2015 Oct 22.