Galiellalactone Shows Promise for Treating Intractable Prostate Cancer

A promising new treatment for prostate cancer that has become resistant to hormone, radiation, and drug therapy is based on the STAT3 inhibitor galiellalactone.

The STAT protein family regulates many aspects of cell growth, survival, and differentiation. Dysregulation of this signaling pathway is frequently observed in primary tumors and leads to increased angiogenesis and enhanced tumor survival. Knockout studies have provided evidence that STAT proteins are involved in the development and function of the immune system and play a role in maintaining immune tolerance and tumor surveillance. STAT3-deficient mouse embryos cannot develop beyond embryonic day seven, when gastrulation initiates. It appears that at these early stages of development, STAT3 activation is required for self-renewal of embryonic stem cells. Constitutive STAT3 activation is associated with various human cancers and commonly suggests poor prognosis. It has antiapoptotic as well as proliferative effects.

Galiellalactone is a hexaketide metabolite, which selectively inhibits IL-6 induced secreted embryonic alkaline phosphatase (SEAP) expression by blocking the binding of activated STAT3 dimers to DNA. In addition, galiellalactone can inhibit STAT3 without affecting tyrosine and serine phosphorylation of the STAT3 transcription factor. Furthermore, studies indicate that galiellalactone may be an ideal tool in dissecting the JAK/STAT pathways due to its selective inhibition of STAT3.

In the current study, investigators at Lund University (Sweden) examined the effect of galiellalactone on prostate cancer stem cell-like cells. They focused on the expression of aldehyde dehydrogenase (ALDH) as a marker for cancer stem cell-like cells in different human prostate cancer cell lines and the effects of galiellalactone on ALDH expressing (ALDH+) prostate cancer cells.

They reported in the July 11, 2011, online edition of the journal PLoS ONE that in contrast to ALDH− cells, ALDH+ prostate cancer cells showed cancer stem cell-like characteristics such as increased self-renewing and colony forming capacity and tumorigenicity. In addition, ALDH+ cells showed an increased expression of putative prostate cancer stem cell markers, and ALDH+ cells expressed phosphorylated STAT3. Galiellalactone treatment decreased the proportion of ALDH+ prostate cancer cells and induced apoptosis of ALDH+ cells.

Senior author Dr. Anders Bjartell, professor of medicine at Lund University, said, “Prostatic tumors are thought to consist only of about 0.1% cancer stem cells, but if you are not successful in eradicating that tumor cell population, there is a risk of subsequent uncontrolled growth of the tumor. The cancer stem cells are often unresponsive to both hormonal treatment and to chemotherapy, so it is essential to develop a direct treatment towards all types of cancer cells. Targeting the STAT3 pathway in prostate cancer cells, including prostate cancer stem cell-like cells, is a promising therapeutic approach and galiellalactone is an interesting compound for the development of future prostate cancer drugs.”

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