Submitted July 5, 2006
Accepted October 28, 2006
Chaetocin, a promising new anti-myeloma agent with in vitro and in vivo activity mediated via imposition of oxidative stress
Crescent R Isham, Jennifer D Tibodeau, Wendy Jin, Ruifang Xu, Michael M Timm, and Keith C Bible*
Division of Medical Oncology, Dept of Oncology, Mayo Clinic, Rochester, MN
* Corresponding author; email: bible.keith{at}mayo.edu.
Chaetocin, a thiodioxopiperazine natural product previously unreported to have anti-cancer effects, was found to have potent anti-myeloma 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 anti-myeloma 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 anti-cancer activity appears mediated primarily through the imposition of oxidative stress and consequent apoptosis induction. Moreover, the selective anti-myeloma 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 anti-myeloma therapeutic.
