Chaetocin: a promising new antimyeloma agent with in vitro and in vivo activity mediated via imposition of oxidative stress

Abstract

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.

The Suv39H1 methyltransferase inhibitor chaetocin causes induction of integrated HIV-1 without producing a T cell response

“…Consistent with the finding that chaetocin does not cause global T-cell activation, we find that NFjB p65 does not bind the LTR in chaetocin-treated cells. Chaetocin was shown to cause oxidative stress in myeloma cells [22], and importantly oxidative stress of Jurkat cells induces expression of HIV-1, apparently through activation of NFjB [23]. Because we do not observe an effect of chaetocin on association of NFjB p65 with the LTR, it is possible that this compound does not produce a comparable stress response in the Jurkat cell line.…”

Antihepatoma activity of chaetocin due to deregulated splicing of hypoxia-inducible factor 1α pre-mRNA in mice and in vitro

“…We first examined whether Suv39H1, oxidative stress, or thioredoxin reductase-1 is involved in HIF-1a suppression. [12][13][14] However, HIF-1a expression and the chaetocin effect occurred regardless of these factors (Fig. 4A-C).…”

“…12 Recently, it was also demonstrated that chaetocin induces apoptosis of myeloma cells and retards the growth of myeloma xenografts. 13 Mechanistically, it was proposed that chaetocin produces oxidative damage in myeloma cells by inhibiting the antioxidant enzyme thioredoxin reductase. 14 However, little is known about the effects of chaetocin on solid tumors, and thus we tested the anticancer activity of chaetocin against solid tumors.…”

Anti-leukemia activity of chaetocin via death receptor-dependent apoptosis and dual modulation of the histone methyl-transferase SUV39H1

“…18 Chaetocin displayed anticancer properties against multiple myeloma via oxidative stress induction. 19 SUV39H1 is the main HMT responsible for the accumulation of histone H3 containing a tri-methyl group at its lysine 9 position (H3K9me3) in heterochromatin. SUV39H1 interacts with proto-oncogenes such as AML1, EVI-1 and PML-RARa, which play critical roles in the development of AML, influencing the transcriptional repression of target genes involved in hematopoietic differentiation and bone marrow immortalization.…”