<title>1. INTRODUCTION</title> <p>The primary effects of thiazolidinedione, a peroxisome proliferator-activated
receptor <italic>γ</italic> (PPAR<italic>γ</italic>) agonist, are the reduction of insulin resistance
and improvement of insulin sensitivity, resulting in reduction of fasting
plasma glucose, insulin, and free fatty acid levels [##UREF##0##1##].</p> <p>Cholangiocarcinoma
is a predominantly fatal cancer, which can be difficult to treat. We reported previously that administration of the thiazolidinedione, pioglitazone, in a 73-year-old male
patient who developed cholangiocarcinoma with cholangiohepatitis and diabetes
improved not only diabetic control, but also the tumor-induced
cholangiohepatitis, and improved the patient's quality of life [##REF##17938528##2##]. One and
half years after treatment, the patient again showed deterioration of
cholangiohepatitis and diabetic control. He finally died of obstructive jaundice.</p> <p>There are two possible mechanisms to
explain the initial improvement of hepatitis in our case: the PPAR<italic>γ</italic> ligand may have directly suppressed the
abnormal cell growth, or the PPAR<italic>γ</italic> ligand may have indirectly suppressed tumor growth after the ligand
improved hepatitis and/or diabetes.</p> <p>In this review, we discuss the mechanisms
of the temporary beneficial effects of the agent, especially the above two
possibilities, with regard to the literature concerning PPAR<italic>γ</italic> and cholangiohepatitis. In addition, we
also discuss the positive choice of thiazolidinedione, despite elevated serum
concentrations of hepatic enzymes.</p>
<p>Recommended by Dipak Panigrahy</p> <p>Cholangiocarcinoma is a predominantly fatal cancer, which can be difficult to treat. It has been reported that the administration of pioglitazone temporarily improved not only diabetic control, but also bile duct carcinoma-induced cholangiohepatitis. Pioglitazone is considered to have both direct and indirect mechanisms of action on the tumor-related hepatitis. Several molecules induced by thiazolidinedione, including Smad pathway-related molecules, adipokines, and other lipid metabolism-related proteins, may directly or indirectly suppress tumor development and/or tumor-induced cholangiohepatitis. Although the most frequent and critical side effect of thiazolidinedione is drug-induced hepatitis, it can probably be avoided by careful monitoring of serum hepatic enzyme levels. Thiazolidinedione should be considered for management of tumor-induced hepatitis in the presence of diabetes unless severe side effects occur.</p>
<title>2. DIRECT EFFECTS ON THE DEVELOPMENT OF CHOLANGIOCARCINOMA</title> <p>These mechanisms
were supported by the results of basic experiments using various
cholangiocarcinoma cell lines [##REF##12829999##3##–##REF##15294900##6##]. PPAR<italic>γ</italic> ligand mediates the inhibition of
cholangiocarcinoma cell growth through p53-dependent mechanisms [##REF##12829999##3##]. The PPAR<italic>γ</italic> ligand, 15-deoxy-delta 12,14-PGJ2,
induces apoptosis in cholangiocarcinoma cell lines although regulation of
apoptosis-related protein expression varies [##REF##14612959##4##, ##REF##16927143##5##], while artificial regulation
of PPAR<italic>γ</italic>
expression in cholangiocarcinoma cell lines suggests that PPAR<italic>γ</italic> may actually promote tumor cell growth viathe Smad pathway [##REF##15294900##6##]. It has been reported that PPAR<italic>γ</italic> ligands can suppress proliferation and
induce apoptosis although PPAR<italic>γ</italic> itself may have divergent effects on cellular growth in
cholangiocarcinoma cell lines [##REF##1355757##7##].</p> <title>3. INDIRECT EFFECTS ON THE DEVELOPMENT OF CHOLANGIOCARCINOMA</title> <p>Thiazolidinedione seems not to improve
insulin sensitivity and glucose disposal by direct effects on either the liver
or muscle. PPAR<italic>γ</italic> is
expressed preferentially in adipose tissue, and its levels of expression in the
liver and skeletal muscle are low [##REF##9231657##8##]. Thus, it is more likely that the primary
effects of these drugs are on adipose tissue, followed by secondary benefits on
other target tissues of insulin [##REF##11861525##9##]. In our case, there was no evidence that
pioglitazone directly reduced the tumor size. In contrast, cholangiohepatitis
was improved by administration of this agent. In addition, the progressive
cholangiohepatitis was probably related to the cholangiocarcinoma. In general,
cholangiocarcinoma development is based possibly upon the cytotoxicity of bile
constituents, that is, cytotoxic bile acids and lysolecithins. These humoral
factors may affect tumor progression. Thus, it was suggested that pioglitazone
indirectly improves cancer-mediated inflammation, such as cholangiohepatitis,
rather than directly suppressing tumor growth.</p> <p>As mentioned above, it is now generally
accepted that adipose cells send molecular signals, including cytokines, to
other tissues. Thus, it is possible that PPAR<italic>γ</italic> activation controls one or more genes that regulate systemic tumor
promotion (see ##FIG##0##Figure 1##). The interesting candidate genes in this regard are
TNF-<italic>α</italic>, adiponectin, and
leptin. Other lipid-related genes regulated by PPAR<italic>γ</italic> ligands, such as lipoprotein lipase and
fatty acid binding protein, may also control tumor development [##REF##9568680##10##].</p> <title>3.1. TNF-<italic>α</italic>
</title> <p>Thiazolidinedione reduces TNF-<italic>α</italic> expression in human and rodent adipocytes
[##REF##12670740##11##]. A series of studies using cholangiocarcinoma cell lines demonstrated that
TNF-<italic>α</italic> itself attenuates
the growth of cholangiocarcinoma cells and induces apoptosis [##REF##12670740##11##–##REF##11870367##13##]. However,
several recent studies have demonstrated that TNF-<italic>α</italic> promotes invasiveness and accelerates
migration of cholangiocarcinoma cells [##REF##16565491##14##–##REF##15723721##16##]. These observations imply that the suppression of TNF-<italic>α</italic> production may attenuate the progressive invasion of tumor cells into healthy hepatobiliary cells.</p> <title>3.2. Adiponectin and leptin</title> <p>PPAR<italic>γ</italic> agonists have been reported to increase the expression and circulating
levels of adiponectin, an adipocyte-derived protein with insulin-sensitizing
activity [##UREF##1##17##], in diabetic rodents and in patients with type 2 diabetes [##REF##11815513##18##]. There have been many reports, especially in breast cancer, that adiponectin
plays roles in the inhibition of tumor cell growth [##REF##17981890##19##]. The expression of
leptin, a suppressor of feeding behavior, is negatively regulated by
thiazolidinediones [##REF##8770873##20##]. Leptin has been reported to induce tumor development
in breast cancer [##REF##17639037##21##], suggesting that suppression of leptin secretion may
reduce tumor progression.</p> <title>3.3. Other lipid-related proteins</title> <p>Other lipid-related proteins, such as lipoprotein lipase
(LPL) and fatty acid binding proteins (FABPs), are positively regulated by the
PPAR<italic>γ</italic> ligand GW1929 [##REF##11181544##22##]. Although there have been no studies related to cholangiocarcinoma and these lipid-associated proteins, there is a great deal of evidence that the
proteins promote reduction of tumor growth. Intestinal polyp formation was
suppressed by increasing LPL activity [##REF##16606335##23##]. As FABPs play roles not only as
lipid chaperones but also as free radical scavengers, the molecules may affect
tumor progression through the oxidative stress pathways. The protein expression
of liver FABP was reduced in neoplastic lesions of CuZn superoxide
dismutase-deficient mice [##REF##17514684##24##]. It has been reported that FABP reduces cellular
damage from hypoxia/reoxygeneration [##REF##16175609##25##]. These lipid-related proteins may also play roles in the reduction of tumor growth and/or suppression of
tumor-mediated liver damage.</p> <title>4. HEPATIC SIDE EFFECTS</title> <p>The most frequent and
critical side effect of thiazolidinedione that must be taken
into consideration before starting thiazolidinedione administration in cases of
cholangiocarcinoma is drug-induced hepatitis. Although some data are available from animal studies suggesting that
hepatic toxicity may be a characteristic of the thiazolidinedione class [##REF##11754868##26##],
current clinical evidence indicates that pioglitazone treatment does not result
in liver toxicity [##REF##11768834##27##]. However, this agent causes mild transient increases in
serum ALT levels. The FDA recommends monitoring ALT levels and not using these
drugs in patients with liver disease [##REF##15611492##28##]. Moreover, it was reported that
patients receiving pioglitazone may develop serious liver injury and should be
monitored for evidence of hepatitis [##REF##11900497##29##].</p> <p>Unlike other
existing antidiabetic medications that show a very rapid onset of activity,
pioglitazone and rosiglitazone exhibit a characteristic delay of 4–12 weeks in the
onset of their therapeutic effects. It has been suggested that thiazolidinedione
should be continued for at least one month to obtain results. In our case,
initial improvement of the elevated hepatic enzymes was observed two weeks
after starting administration of this agent. These data indicate that the
effectiveness in cases of tumor-related hepatitis could be assessed within two
weeks rather than 4–12 weeks when
diabetic control is obtained.</p> <title>5. PERSPECTIVES</title> <p>Taken together with
these considerations, as PPAR<italic>γ</italic> ligands are probably effective in the suppression
of tumor development, especially on the reduction of tumor invasiveness through
molecular signals from adipocytes, thiazolidinedione should be chosen not only for diabetic control, but
also as an attenuator of tumor progression in patients with diabetes.
Drug-induced hepatitis can be avoided by meticulous monitoring of serum hepatic
enzyme levels.</p>
<title>ACKNOWLEDGMENTS</title> <p>The authors gratefully
acknowledge Ms. Izumi Kinoshita for her excellent secretarial assistance. They also
thank Takeshi Inagaki from the Departments of Molecular Biology and
Pharmacology at the University of Texas Southwestern Medical Center for helpful
information.</p>
<fig id="fig1" position="float"><label>Figure 1</label><caption><p>Inhibitory effects of PPAR<italic>γ</italic> ligand on the
development of cholangiocarcinoma. PPAR<italic>γ</italic> ligand directly suppresses tumor progression through p53 and Smad pathways (red arrow) and also stimulates adipocyte and
hepatobiliary cells (gray arrow). Secretion of adipokines (TNF-<italic>α</italic>, adiponectin, and leptin) and production of lipid-related proteins (FABP and LPL) are regulated by PPAR<italic>γ</italic> ligand. Up- and downregulation of various gene signals from adipocytes (yellow line) and hepatobiliary cells (broken line) promoted
suppression of tumor growth. As a result, PPAR<italic>γ</italic>
indirectly suppressed tumor growth of cholangiocarcinoma through adipocytes and
hepatobiliary cells. Currently, evidence of suppressive signals from
hepatobiliary cells to cholangiocarcinoma is unavailable (broken line). FABP:
fatty acid binding protein, LPL: lipoprotein lipase, TNF-<italic>α</italic>: tumor necrosis factor-<italic>α</italic>.</p></caption></fig>
<graphic xlink:href="PPAR2008-587401.001"/>
[{"label": ["1"], "surname": ["Mudaliar", "Henry"], "given-names": ["S", "RR"], "article-title": ["New oral therapies for type 2 diabetes mellitus: the glitazones or insulin sensitizers"], "italic": ["Annual Review of Medicine"], "year": ["2001"], "volume": ["52"], "fpage": ["239"], "lpage": ["257"]}, {"label": ["17"], "surname": ["Yamauchi", "Kamon", "Waki"], "given-names": ["T", "J", "H"], "article-title": ["The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity"], "italic": ["Nature Medicine"], "year": ["2001"], "volume": ["7"], "issue": ["8"], "fpage": ["941"], "lpage": ["946"]}]
PPAR Res. 2008 Jul 6; 2008:587401