Chaetocin: a promising new antimyeloma agent with in vitro and in vivo activity mediated via imposition of oxidative stress.
Chaetocin, a thiodioxopiperazine natural product previously unreported to have anticancer effects, was found to have potent antimyeloma activity in IL-6-dependent and -independent myeloma cell lines in freshly collected sorted and unsorted patient CD138(+) myeloma cells and in vivo. Chaetocin largely spares matched normal CD138(-) patient bone marrow leukocytes, normal B cells, and neoplastic B-CLL (chronic lymphocytic leukemia) cells, indicating a high degree of selectivity even in closely lineage-related B cells. Furthermore, chaetocin displays superior ex vivo antimyeloma activity and selectivity than doxorubicin and dexamethasone, and dexamethasone- or doxorubicin-resistant myeloma cell lines are largely non-cross-resistant to chaetocin. Mechanistically, chaetocin is dramatically accumulated in cancer cells via a process inhibited by glutathione and requiring intact/unreduced disulfides for uptake. Once inside the cell, its anticancer activity appears mediated primarily through the imposition of oxidative stress and consequent apoptosis induction. Moreover, the selective antimyeloma effects of chaetocin appear not to reflect differential intracellular accumulation of chaetocin but, instead, heightened sensitivity of myeloma cells to the cytotoxic effects of imposed oxidative stress. Considered collectively, chaetocin appears to represent a promising agent for further study as a potential antimyeloma therapeutic.
Isham
Crescent R
CR
Division of Medical Oncology, Department of Oncology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
Tibodeau
Jennifer D
JD
Jin
Wendy
W
Xu
Ruifang
R
Timm
Michael M
MM
Bible
Keith C
KC
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use* / Q000633:toxicity; D001854:Bone Marrow Cells / Q000166:cytology; D019070:Cell Lineage; D002470:Cell Survival / Q000187:drug effects; D018920:Coculture Techniques; D003907:Dexamethasone / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000473:pathology; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D016513:Mice, SCID; D046529:Microscopy, Electron, Transmission; D009101:Multiple Myeloma / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D018384:Oxidative Stress; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use / Q000633:toxicity; D053668:Syndecan-1 / Q000378:metabolism; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D006657:Histones; D015850:Interleukin-6; D010879:Piperazines; D053668:Syndecan-1; C002511:chaetocin; D003907:Dexamethasone; D004317:Doxorubicin; D005978:Glutathione