Comparison of the efficacy of gossypol acetate enantiomers in rats with uterine leiomyoma

The IL (interleukin)-6-type cytokines IL-6, IL-11, LIF (leukaemia inhibitory factor), OSM (oncostatin M), ciliary neurotrophic factor, cardiotrophin-1 and cardiotrophin-like cytokine are an important family of mediators involved in the regulation of the acute-phase response to injury and infection. Besides their functions in inflammation and the immune response, these cytokines play also a crucial role in haematopoiesis, liver and neuronal regeneration, embryonal development and fertility. Dysregulation of IL-6-type cytokine signalling contributes to the onset and maintenance of several diseases, such as rheumatoid arthritis, inflammatory bowel disease, osteoporosis, multiple sclerosis and various types of cancer (e.g. multiple myeloma and prostate cancer). IL-6-type cytokines exert their action via the signal transducers gp (glycoprotein) 130, LIF receptor and OSM receptor leading to the activation of the JAK/STAT (Janus kinase/signal transducer and activator of transcription) and MAPK (mitogen-activated protein kinase) cascades. This review focuses on recent progress in the understanding of the molecular mechanisms of IL-6-type cytokine signal transduction. Emphasis is put on the termination and modulation of the JAK/STAT signalling pathway mediated by tyrosine phosphatases, the SOCS (suppressor of cytokine signalling) feedback inhibitors and PIAS (protein inhibitor of activated STAT) proteins. Also the cross-talk between the JAK/STAT pathway with other signalling cascades is discussed.

Uterine leiomyomas (fibroids or myomas), benign tumours of the human uterus, are the single most common indication for hysterectomy. They are clinically apparent in up to 25% of women and cause significant morbidity, including prolonged or heavy menstrual bleeding, pelvic pressure or pain, and, in rare cases, reproductive dysfunction. Thus, both the economic cost and the effect on quality of life are substantial. Surgery has been the mainstay of fibroid treatment, and various minimally invasive procedures have been developed in addition to hysterectomy and abdominal myomectomy. Formation of new leiomyomas after these conservative therapies remains a substantial problem. Although medications that manipulate concentrations of steroid hormones are effective, side-effects limit long-term use. A better approach may be manipulation of the steroid-hormone environment with specific hormone antagonists. There has been little evidence-based evaluation of therapy. New research into the basic biology of these neoplasms may add new treatment options for the future as the role of growth factors and genetic mutations in these tumours are better understood.

Impaired apoptosis is both critical in cancer development and a major barrier to effective treatment. In response to diverse intracellular damage signals, including those evoked by cancer therapy, the cell's decision to undergo apoptosis is determined by interactions between three factions of the Bcl-2 protein family. The damage signals are transduced by the diverse 'BH3-only' proteins, distinguished by the BH3 domain used to engage their pro-survival relatives: Bcl-2, Bcl-x(L), Bcl-w, Mcl-1 and A1. This interaction ablates pro-survival function and allows activation of Bax and Bak, which commit the cell to apoptosis by permeabilizing the outer membrane of the mitochondrion. Certain BH3-only proteins (e.g. Bim, Puma) can engage all the pro-survival proteins, but others (e.g. Bad, Noxa) engage only subsets. Activation of Bax and Bak appears to require that the BH3-only proteins engage the multiple pro-survival proteins guarding Bax and Bak, rather than binding to the latter. The balance between the pro-survival proteins and their BH3 ligands regulates tissue homeostasis, and either overexpression of a pro-survival family member or loss of a proapoptotic relative can be oncogenic. Better understanding of the Bcl-2 family is clarifying its role in cancer development, revealing how conventional therapy works and stimulating the search for "BH3 mimetics" as a novel class of anticancer drugs.