title: CYT997 causes apoptosis in human multiple myeloma.
abstract: Multiple Myeloma (MM) is an incurable malignancy of mature plasma cells. Microtubule targeting agents (MTAs) are an established class of drug that include many conventional and some novel compounds. MTAs function by inhibiting the polymerisation or depolymerisation of microtubules (MTs) within the cell, disrupting various important cellular functions. We have investigated pre-clinically the novel tubulin polymerisation inhibitor CYT997 for the potential treatment of MM. Here we demonstrate the promising anti-myeloma activity of CYT997 as evidenced by tubulin disruption, inhibition of growth and proliferation, cell cycle arrest and most importantly apoptosis of both human myeloma cell lines (HMCLs) and primary MM cells using nanomolar drug concentrations. CYT997 also synergises with bortezomib to produce more potent anti-MM activity. These in vitro observations were validated in vivo by the ability of CYT997 to significantly prolong survival in a murine model of aggressive systemic myelomatosis. These findings provide a basis for continuing pre-clinical and clinical investigations into the anti-MM effects of CYT997.
authors.affiliation: Myeloma Research Group, Malignant Haematology and Stem Cell Transplantation, South Block, Alfred Hospital, Prahran, Victoria, Australia.
authors.forename: Katherine
authors.initials: K
authors.lastname: Monaghan
authors.forename: Tiffany
authors.initials: T
authors.lastname: Khong
authors.forename: Gregg
authors.initials: G
authors.lastname: Smith
authors.forename: Andrew
authors.initials: A
authors.lastname: Spencer
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D005455:Fluorescent Antibody Technique; D016195:G2 Phase / Q000187:drug effects; D006801:Humans; D051379:Mice; D008938:Mitosis / Q000187:drug effects; D009101:Multiple Myeloma / Q000473:pathology*; D058105:Polymerization / Q000187:drug effects; D011719:Pyrazines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D016019:Survival Analysis; D013997:Time Factors; D014404:Tubulin / Q000378:metabolism
chemical_list: D001897:Boronic Acids; C543949:CYT997; D011719:Pyrazines; D011725:Pyridines; D011743:Pyrimidines; D014404:Tubulin; D000069286:Bortezomib