1. Introduction
A redox disequilibrium has been recognized in recent
years as a specific vulnerability of various tumor cells (1–3). By
exacerbating the oxidative stress, pro-oxidant drugs achieve
antineoplastic activity in a multitude of cancer cells (1,4–6).
Non-malignant cells, with their high anti-oxidant capacity, are
largely resistant to the same degree of deviation from the redox
equilibrium resulting in a high selectivity of such drugs for tumor
cells (2,4–7). In
the present review, Taurolidine is described as a redox-directed
cancer therapeutic with a broad spectrum of antineoplastic action.
In first clinical application in surgical oncology, Taurolidine was
well tolerated in patients with glioblastoma and gastrointestinal
cancers (8–13). In support of the ROS stress pathway
being an effective target for broad antineoplastic action, the
anticancer activity of Piperlongumine, a plant-derived experimental
agent (14,15), is briefly outlined.
2. Redox-directed cancer therapeutics
Cancer arises through a multistep, mutagenic process
(‘oncogene dependency’) whereby cancer cells acquire a common set
of properties that enable tumor cells to proliferate and
disseminate metastases (16). As
an adaptive response, non-oncogenic pathways such as the oxidative
stress response pathways, are also affected (1,2).
Reactive oxygen species (ROS), the key mediators of cellular
oxidative stress involved in cancer initiation and progression,
have recently emerged as promising targets for anticancer drug
development. Cancer cells have been reported to harbor elevated
levels of ROS and the ability to cope with chronically elevated
levels of cellular stress is compromised in a multitude of cancer
cells (1–3,17).
This specific vulnerability of various tumor cells was termed
‘non-oncogene dependency’ or ‘non-oncogene addiction’ (1,4,14).
Importantly, this dependency may not be shared by many
non-transformed cells (3–5,7).
Their basal ROS levels are low and their anti-oxidant capacity is
robust due to the activation of Nrf2, the master regulator of
anti-oxidant responses which includes the induction of anti-oxidant
enzymes such as catalase or glutathione-S-transferase (3,5,7).
In keeping with this hypothesis, small molecular
weight pro-oxidant drugs, which enhance the oxidative stress in
tumor cells, are considered as potential antineoplastic agents
(2,3,6,15).
In contrast, due to the lower basal ROS levels and elevated
anti-oxidant capacity, the same pro-oxidant deviation from redox
homeostasis would be tolerated by non-malignant cells leading to
minimal side-effects (1–3,6,14).
In the age of molecularly targeted therapy, drugs
with pleiotropic actions such as redox-directed agents, frequently
find limited enthusiasm based on the expectation of off-target
toxic effects. However, as exemplified in this review, at least
some redox-directed agents appear to act selectively on tumor
cells. In addition, recent research suggests that it is exactly the
pleiotropic mode of action which seems to be uniquely tailored to
overcome cancer cell drug resistance originating from a redundancy
of oncogenic signaling and rapid mutation (3,6).
3. Broad-spectrum antineoplastic activity of
Taurolidine
Taurolidine, first synthesized in the 1970s
(18) as bis(1,1-
dioxoperhydro-1,2,4-thiadizinyl-4)methane, was originally known for
its antibacterial and anti-toxin (exo/endotoxin) activity and was
tested clinically in the 1980’s in the treatment of severe surgical
infections, abdominal sepsis and peritonitis (10,11,13).
Its antineoplastic activity became apparent in colony forming
assays, in which dissociated cells were seeded at very low density
and incubated for 2 to 4 weeks. Taurolidine potently prevented cell
proliferation (EC50, 1 to 7 μg/ml) as shown for glioma
cell lines (19–21) as well as ex vivo human
glioblastoma cells (19). In
addition, at higher concentrations, Taurolidine induced acute
cytotoxicity (EC50, 40 to 80 μg/ml), tested at 24–72 h
incubation, as shown for a multitude of cultured tumor cell lines
such as mesothelioma (22–24), prostate (21,25),
glioblastoma (19,20,26,27),
ovarian (21,28), leukemia (28), colon (21,29–36),
melanoma (21,37,38),
osteosarcoma (40,41), pancreatic (41), lung (21), esophageal (42) and fibrosarcoma (41,43)
as partly summarized by Jacobi et al (44). The effectiveness of Taurolidine
in vitro was largely confirmed in vivo using various
tumor cell lines as xenografts such as mesothelioma (23), prostate (25), ovarian (21,45),
colon (29–31,34,35)
and melanoma (37,46) as well as melanoma cells in a
metastatic tumor model (46).
4. ROS-dependent cytotoxicity of
Taurolidine
As first demonstrated in glioblastoma cells
(19), a ROS-dependent mechanism
of Taurolidine-induced cell death became apparent in many tumor
cell types. Taurolidine increased the level of ROS as shown in
glioblastoma (19) and
mesothelioma cells (22,24). The reducing agent N-acetylcysteine
(NAC) was able to block or strongly reduce the cytotoxicity in
nearly all tumor cells such as glioblastoma (20), mesothelioma cells (22,24),
colon carcinoma HT29 cells (47)
and Chang liver cells (47)
although not in fibrosarcoma HT1080 cells (47). Addition of glutathione similarly
prevented cytotoxicity as shown for mesothelioma cells (22). Conversely, a reduction of the
glutathione level with DL-buthionin-(S,R)-sulfoximine (BSO)
enhanced the ability of Taurolidine to induce cell death as shown
for glioblastoma cells (20) as
well as colon and pancreas carcinoma cells (47). These results underline the central
role of ROS in triggering the Taurolidine-induced programmed cell
death. Molecularly, Taurolidine may interfere with regulators of
redox and ROS homeostasis such as glutathione-S transferase 1.
5. Taurolidine and cancer stem cells
In most tumors, the hierarchical model of tumor
formation is thought to be operative with cancer stem cells (CSC)
contributing to self-renewal and regrowth after debulking of tumor
mass by surgery or radiation (16)
e.g., in glioblastoma (48).
Taurolidine exerted potent cytotoxic activity against murine and
human glioma CSCs with ED50, 12±2 μg/ml and
EC50, 13±2 μg/ml, respectively. The CSCs were isolated
by the formation of neurospheres from either the murine SMA 560
glioma cell line or from tissue resected from newly diagnosed WHO
grade IV glioblastoma patients (KF, unpublished data). These
results extend the effectiveness of redox-directed cytotoxicity to
CSCs and may strengthen the therapeutic potential of
Taurolidine.
6. Sparing of normal cells by
Taurolidine
Non-tumor cells in vitro such as bone marrow
cells (28), NIH-3T3 fibroblasts
(21), non-neoplastic mesothelial
cells (22) were not affected by
Taurolidine under conditions of tumor cell cytotoxicity. Similarly,
in vivo, physiological cell proliferation such as
leukopoiesis or erythropoiesis (28,31,44)
were practically not affected by Taurolidine. The apparent
selective induction of cytotoxicity in cancer cells distinguishes
Taurolidine from other molecules that partly affect ROS levels,
such as paclitaxel, bleomycin, cisplatin or the glutathione
synthesis inhibitor BSO (6,49–53).
7. Good tolerability of Taurolidine in
patients
Initially, Taurolidine was tested as an
intraperitoneal and intravenous adjunct in the treatment of severe
surgical infections (sepsis, peritonitis, pancreatitis), exploiting
its activity against antibiotic-resistant bacteria and bacterial
toxins. Taurolidine showed good tolerability (10,11,13).
In the first clinical experiences with cancer patients in surgical
oncology, Taurolidine was likewise well tolerated. In a first case
report, a patient with gastric cancer re-recurrence was
palliatively treated with 2% Taurolidine i.v. for 39 cycles, each
cycle consisting of 7 days of treatment per month (300 mg/kg body
weight per day). The patient was in good clinical condition as
shown by the relevant blood parameters which included an
undisturbed leukopoesis and thrombopoesis and no sign of toxicity
(9). In a clinical experience with
two patients with progressive, non-resectable glioblastoma and
conventional therapy, the neurological condition and the quality of
life improved in both patients with no sign of tumor progression
(‘partial remission’) following two cycles of 21 days each with 2%
Taurolidine i.v. (20 g/day) (8).
In 11 patients with progresssive metastatic melanoma,
co-administration of Taurolidine with high rIL-2 enhanced the
tolerability of this regime (54).
In a multicenter prospective randomized trial, patients with
different resectable gastrointestinal (GI) cancers (20 patients
each with colon, pancreas or stomach cancer) were treated with a
perioperative lavage (2×10 min) consisting of 0.5%
Taurolidine/heparin versus 0.25% povidone- iodine (control).
Taurolidine resulted in a reduction of inflammatory cytokines
(IL-1, IL-6, IL-10) at 2 and 6 h as measured in peritoneal fluid
compared to pre-resection levels (12). There was no change in serum
leukocytes and the perioperative complications did not differ. Up
to now, the number of GI cancer patients in each group has remained
insufficient for a statistical analysis of disease outcome
following Taurolidine treatment (12). Nevertheless, in these oncological
surgical interventions, Taurolidine did not interfere with
post-operative wound healing, which was also demonstrated in a
study on the use of Taurolidine in coronary artery bypass grafting
in 60 patients (55). These
findings confirmed previous findings in rats in which the scar
tissue biopsies were examined macroscopically and
histopathologically following Taurolidine treatment (56). The perioperative use of Taurolidine
solution (2%) in surgical oncology (57) promises to be of special benefit as
it is administered at the earliest possible therapeutic time
window. Perioperatively, circulating tumor cells, which correlate
negatively with disease free survival and overall survival
(58), would be the prime targets
for Taurolidine. By its ability to be cytotoxic to tumor cells and
tumor stem cells, perioperative Taurolidine promises to reduce
micrometastases and increase survival, as substantiated in a
pancreatic cancer model (59). The
majority of clinical studies relates to the intraperitoneal
administration of Taurolidine, especially in the setting of
peritonitis (11,13). In intravenous studies, vein
irritation at high doses has been experienced, necessitating direct
central administration or peripherally via a PICC line (57).
8. Potency of action and plasma levels in
patients
Due to its short half-life in man (60) Taurolidine is usually administered
by intravenous infusion (2% Taurolidine). When administered i.v.
intermittently to glioblastoma patients, Taurolidine reached a
maximal plasma level of 83±18 μg/ml (61), which is similar to peak values
obtained in acutely treated healthy volunteers (60). This plasma concentration is
expected to be clinically effective. It is about 20 times higher
than the antiproliferative effective concentration of Taurolidine
and is in the range of its cytotoxic potency.
9. Mechanisms of antineoplastic action
The ROS-dependent induction of programmed cell death
by Taurolidine is based on a mixed type of cellular signaling, in
particular the induction of caspase-independent apoptosis but also
autophagy and programmed necrosis (necroptosis) (Fig. 1).
Apoptosis
Induction of apoptosis by Taurolidine was first
shown in ovarian tumor cells (21), also in mesothelioma cells (1,24)
but was most extensively studied in glioma cells (19,20,26,27).
Within minutes of incubation with Taurolidine, the ROS-induced
mitochondrial stress signaling pathway was activated as shown by
the depolarization and permeabilisation of the mitochondrial
membrane of glioblastoma cells (Fig.
2). Concomitantly, as an inducer of apoptosis, the
mitochondrial apoptosis-inducing factor (AIF) was transduced from
the cytoplasm into the nucleus (Fig.
2) (19). In keeping with the
redox-directed mechanism, this process was completely blocked by
co-incubation with N-acetyl-cysteine (NAC) (19). This reducing agent prevented the
Taurolidine-induced cell death in practically all tumor cells
tested, as described above, supporting the view that induction of
apoptosis is the main mechanism of Taurolidine-induced cytotoxicity
(19,22,24,47).
Other markers of apoptosis included condensation of chromatin,
fragmentation of DNA, externalization of phosphatidylserine and
blebbing of the plasma membrane (Fig.
3) (19–21,23,24,27).
On the molecular level, the signaling pathways
activated by Taurolidine, included the expression of pro-apoptotic
transcription factors, the downregulation of the anti-apoptotoc
regulator Bcl2, as well as the induction of genes involved in the
ER stress response, in protein ubiquitination and in mitochondrial
apoptotic pathways (42,62,63).
Akt (but not Erk1,2) was inhibited (22). Taurolidine acted synergistically
with TRAIL-induced apoptosis (42,63).
In keeping with the ROS-dependent mechanism of action, Taurolidine
was effective independent of whether p53 was mutated or not
(19,20). A significant effect on DNA repair
(PARP) was excluded, since PARP inhibition did not interfere with
the cytotoxicity of Taurolidine (19,20).
Caspase-dependent pathways of apoptosis played a
minor role. In glioblastoma cell lines, but not in ex vivo
glioma cells, cytochrome c translocation was observed only
to a very small extent (19,20).
Nevertheless, after long-term incubation with Taurolidine (up to 48
h), some cytochrome c-dependent caspase activation (caspase
8 and 9) was apparent in prostate, colon and mesothelioma tumor
cell lines since cytotoxicity was partly inhibited by a pan-caspase
inhibitor (23,41,45).
The primary molecular targets of Taurolidine remain to be
identified.
Autophagy
States of cellular stress, including ROS formation,
are known to be strong inducers of autophagy, a caspase-independent
process of cell death. In this lysosomal process, cytoplasm and
intracellular organelles are sequestered into autophagosomes and
delivered to lysosomes for degradation. In glioblastoma cells,
incubation with Taurolidine (6–24 h) induced autophagy in part of
the cells as visualized by the sequestration and lysosomal
degradation of intracellular oganelles using transmission electron
microscopy (20,41). Autophagosomes were also detected by
confocal microscopy (20).
Inhibition by 3-methyl-adenine is likewise in keeping with
autophagy (20). Autophagy
represents an alternative mechanism of cytotoxicity in particular
for apoptosis-resistant tumor cells (64).
Necrosis
The degree of Taurolidine-induced necrosis was
variable. It was negligible in glioma cells but appeared more
prevalent in pancreatic and fibrosarcoma cell lines (47). In glioma cell culture (LN229),
Taurolidine within 24 h killed 90% of the cells as shown by the
complete dissolution of the cell morphology (phase contrast
microscopy before Annexin-V and PI staining). Of these cells, 53%
were apoptotic, only 4.6% were necrotic (19,20).
The latter was largely due to programmed necrosis (necroptosis)
since pretreatment with necrostatin-1, a selective inhibitor of the
receptor-interacting protein kinase RIP1, had some protective
effect (about 40%) (20). The
large number of unstained glioma cells (42%) may point to effects
of Taurolidine beyond the induction of apoptosis and necrosis such
as autophagy, as described above.
10. Supportive anti-angiogenic and
anti-inflammatory activities of Taurolidine
Tumors are able to create a permissive
microenvironment which includes the ability to induce
neo-angiogenesis for maintaining the supply of oxygen and nutrients
(16). Besides the induction of
the programmed cell death, the antineoplastic activity of
Taurolidine includes the inhibition of neo-angiogenesis.
Taurolidine inhibited the adhesion of cultured endothelial cells
(65), reduced the synthesis of
VEGF but not of IL-6 (19,31) and potently inhibited the
VEGF-induced formation of new blood vessels from human endothelial
cells in vitro (lowest active concentration 1.25 μg/ml)
(65). It remains to be seen,
wether Taurolidine, besides its cytotoxic effect on tumor cells,
may interfere with the neovascularization of tumors in
vivo.
Taurolidine also showed anti-inflammatory activity
as demonstrated early on by the suppression of E. coli
endotoxin-induced endotoxemia (66) and the endotoxin-induced increase in
IL-1β and TNFα synthesis in human peripheral blood monocytes
(67) as well as the suppression
of the stimulated release of IL-1β from peritoneal macrophages
(34). There is a strong link
between chronic inflammation and cancer, and NFκB is implicated as
a key component in inflammation-induced tumorigenesis (68). In potentially attenuating this
process, Taurolidine upregulated the NFκB inhibitor NFκBIA in
fibrosarcoma and esophageal cancer cells (42,63).
NFκB also regulates the release of the proinflammatory mediators
IL-1, IL-6 and TNFα. The anti-inflammatory effect of Taurolidine
was proposed to contribute, at least partially, to the attenuation
of perioperative tumorigenesis by diminishing the surgery-related
inflammation as shown in a rat melanoma model (46,57).
11. Piperlongumine, a broad-spectrum
antineoplastic agent
The plant alkaloid Piperlongumine (PL), which was
previously reported to have antibacterial properties (69), was recently shown to display broad
antineoplastic activity by targeting the ROS stress pathway in
tumor cells. PL caused a marked increase in ROS selectively in
cancer cells as shown in four cancer cell lines (incubation for 1
and 3 h) (14). PL
dose-dependently induced cytotoxicity in all 13 different tumor
cell lines tested with half maximal effects being reached at 6–8 μM
(Fig. 4) (14). The increase in ROS in tumor cells
and the cytotoxicity of PL was reduced by co-incubation with the
enzyme catalase or blocked by the addition of NAC (14). PL is thought to interfere with
redox and ROS homeostatic regulators such as glutathione-S
transferase 1 or carbonyl reductase (14). PL, under comparable conditions, did
not cause an increase of ROS or cytotoxicity in normal cells such
as endothelial cells, breast epithelial cells, keratinocytes and
skin fibroblasts (Fig. 4)
(14). The PL-induced killing of a
broad spectrum of tumor cell lines was based on a mixed type of
cellular signaling based largely on the induction of apoptosis
(70) but also of autophagy. The
latter was triggered via the p38 protein kinase ROS stress response
pathway (71). In prostate cells,
inhibition of proliferation included the downregulation of the
transcription factor NFκB (72).
Thus, PL is an interesting broad-spectrum, redox-directed
experimental antineoplastic agent.
12. Conclusions
Taurolidine is a representative of a novel class of
redox-directed, broad-spectrum antineoplastic agents with
tumor-selective cytotoxicity. It induces programmed cell death by
targeting the oxidative stress response pathway which is
compromised in many tumor cells. In initial applications in
surgical oncology, Taurolidine i.v. was largely free of significant
side-effects and merits further clinical evaluation. Applied
perioperatively, Taurolidine promises to reduce circulating tumor
cells, a negative predictor for disease-free survival. Taurolidine
also inhibits VEGF-induced neo-angiogenesis and may therefore
display a dual mode of antineoplastic action. Piperlongumine, an
experimental plant-derived agent, is another redox-directed
broad-spectrum antineoplastic agent with tumor cell
selectivity.
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