The Durk Pearson & Sandy Shaw®
Life Extension NewsTM
Volume 8 No.
1 • January 2005
Possible Induction of Terminal Differentiation of Breast Cancer and Prostate Cancer through PPARgamma
Drugs (thiazolidinediones) that activate the peroxisome-proliferator-activated receptor gamma (PPARgamma) are widely used in the treatment of diabetes, where they improve insulin sensitivity, largely via the stimulation of adipogenesis, whereby preadipocytes differentiate into small adipocytes. (Small adipocytes are much more sensitive to insulin than are large adipocytes stuffed with fat.) Natural agonists (ligands) of PPARgamma include some fatty acids, such as docosahexaenoic acid and oleic acid.
Recent reports suggest that activation of PPARgamma may lead to terminal differentiation of human breast and prostate cancers. The paper on human breast cancer reports that PPARgamma is consistently expressed in metastatic disease and that activation of this nuclear receptor by ligands causes human breast cancer to undergo “dramatic morphological and molecular changes that are characteristic of a more differentiated, less malignant state.”
Keratin 19 and mucin-1 are two proteins whose expression is interpreted as a marker of breast cancer malignancy; they were suppressed by the thiazolidinedione pioglitazone. The authors also report that “… once activation of PPARgamma occurs for several days, the drug can be removed and the cells retain a substantially reduced capacity for clonogenic growth.”
The prostate cancer paper reported that human prostate cancer cells also expressed PPARgamma at “prominent” levels, while normal prostate cells had very low expression. PC-3 human prostate cancer cells cultured with the thiazolidinedione troglitazone* showed “dramatic morphological changes … suggesting that the cells became less malignant.” Moreover, troglitazone decreased by 50% the amount of PSA (prostate-specific antigen) produced by these cells. The authors also studied the culture of human prostate cancer tumors obtained surgically with the same drug and found marked and selective (about 60%) necrosis of the cancer cells, but not the adjacent normal cells.
Another paper reports that PPARgamma ligands are potent inhibitors of angiogenesis, one possible factor in the anticancer effects of PPARgamma induction. In this paper, the authors report that human umbilical vein endothelial cells (HUVEC) express PPARgamma mRNA and protein and that activation of PPARgamma by certain ligands, including ciglitazone (a thiazolidinedione) dose-dependently suppresses HUVEC differentiation into tubelike structures that form early in blood vessel development. Moreover, the PPARgamma ligands also inhibited the proliferation of HUVEC in response to various growth factors. They even found that administration of the PPARgamma natural receptor ligand 15d-PGJ2 in rat cornea prevented vascular endothelial cell growth factor-induced angiogenesis.
It is not clear how activation of PPARgamma could cause all these effects, but even without this knowledge, it still may be useful in treatment. There is much less risk of cytotoxicity with the thiazolidinediones than with many conventional chemotherapeutic agents. However, they are by no means risk-free. Troglitazone itself was removed from the market due to liver toxicity (resulting from fatty accumulation in the liver), where a few patients even required liver transplants as a result. As PPARgamma activators increase adipogenesis (creation of fat cells), it improves insulin sensitivity but may also increase weight. In fact, there is a PPARgamma “paradox” in that both PPARgamma hyperactivity as a result of thiazolidinedione treatment and PPARgamma underactivity due to genetically induced insufficiency protect against obesity-induced insulin insensitivity, leading to the “somewhat perverse, but provocative inference that ‘normal’ amounts of PPARgamma activity, under certain circumstances, promote disease, and that both agonists and antagonists of PPARgamma could be clinically useful. In this regard PPARgamma could be viewed as a ‘thrifty gene,’ promoting fat storage to survive starvation … leading to disease when food is plentiful.” All of the potential consequences of fatty accumulation resulting from long-term use of potent activators of PPARgamma have yet to be discovered, but in the context of serious breast or prostate cancer, these considerations may be of less importance.
- Mueller et al. Terminal differentiation of human breast cancer through PPARgamma. Molec Cell 1:465-70 (1998).
- Kubota et al. Ligand for peroxisome proliferator-activated receptor gamma (troglitazone) has potent antitumor effect against human prostate cancer both in vitro and in vivo. Cancer Res 58:3344-52 (1998).
- Xin et al. Peroxisome proliferator-activated receptor gamma ligands are potent inhibitors of angiogenesis in vitro and in vivo. J Biol Chem 274(13):9116-21 (1999).
- Lowell. PPARgamma: an essential regulator of adipogenesis and modulator of fat cell function. Cell 99:239-42 (1999).