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antagonists).
Additionally, chromenoisoxazole 9 was tested in a
murine model of multiple sclerosis (MS) induced by
TMEV. The Theiler’s murine encephalomyelitis virus
(TMEV) triggers a late-onset demyelinating disease which
presents similar neuroinflammatory processes to human
MS. During the acute inflammatory phase, compound 9
was intraperitoneally administered at a dose of 5 mg/kg
during 7 days. Treatment with 9 led to a remarkable
reduction of inflammatory events in TMEV-infected mice
(25). All these studies demonstrate that chromenoisoxazole
9 has an outstanding neuroprotective profile due to its
capacity to selectively activate CB2R.
In summary, novel fully selective CB2R agonists were
identified through optimization of the chromenopyrazole
scaffold. The lead compound of this series,
chromenoisoxazole 9, has shown antiinflammatory and
neuroprotective properties in vitro and in vivo in various
neurological disorders (murine and rat models of MS and
HD) (25,26). This molecule presents a promising potential
for further drug development, in particular, for the
treatment of neurodegenerative pathologies.
4. A DUAL APPROACH: TARGETING CANCER
WITH CANNABINOID-QUINONES
The development of new effective and safe antitumor
treatments that improve the aggressive current
chemotherapies remains an unmet clinical need. Cancer is
one of the most prevalent diseases and its incidence is
dramatically increasing (27). Within this pathological
panorama, the endocannabinoid system emerges as a
promising anticancer target involved in the modulation of
the main hallmarks of this disease.
?9-THC and its synthetic derivatives have long been
known for their palliative effects in cancer patients. In the clinical trials against cancer are quinone-related
middle 1980´s, dronabinol (Marinol®) and nabilone
(Cesamet®) were approved for the management of
chemotherapy-induced nausea and emesis (28). Their
orexigenic properties and their ability to alleviate pain
associated with cancer have also been widely evidenced
(29–34). However, nowadays, they are only prescribed in
some countries after conventional anti-emetics fail (35,36).
Besides the aforementioned palliative potential of
cannabinoids, more recent research revealed that these
molecules exhibit antitumor effects in numerous in vitro
and in vivo experimental models of cancer (37–39). The
activation of cannabinoid receptors on cancer cells
modulates signaling pathways implicated in cell
proliferation and survival. Even though the underlying
mechanisms are not fully unraveled, there is significant
evidence for the involvement of at least four mechanisms:
direct inhibition of transformed-cell growth through the
suppression of mitogenic signal, induction of apoptosis,
inhibition of tumor angiogenesis and metastasis (40).
The biological role of the ECS in cancer
physiopathology is quite complex and far from being
completely understood. In fact, this endogenous system is
170 @Real Academia Nacional de Farmacia. Spain
Paula Morales, Pilar Goya, Nadine Jagerovic
upregulated in neoplasms compared with non-tumor tissue
(38,40–42). However, these observations are tumor type-
specific and therefore, further research is needed to
understand the regulation of cannabinoid receptor
expression in each type of cancer (37,41).
With regard to the clinical translation of the antitumor
properties of cannabinoids, a pilot clinical trial has been
reported so far (43), whereas a few more are presently in
progress. In this phase I pilot trial, the effects of
intratumoral administration of ?9-THC were studied in
nine patients with glioblastoma multiforme, who had failed
surgical therapy and radiotherapy and exhibited clear
evidence of tumor progression. The results obtained in this
study suggested that cannabinoid treatment reduced tumor
growth rate (43). Nonetheless, more extensive clinical
studies are needed to extract significant conclusions that
reinforce the potential utility of cannabinoids as anticancer
therapeutics.
Among other pharmacological approaches for cancer
treatment, cytotoxic quinones represent an important group
of antineoplastic drugs. Antitumor properties of quinones
have been widely reported and are still the focus of much
research (44,45). The cytotoxic activity of quinoid
derivatives can be accounted for their fast redox cycling
potential and Michael acceptor properties (46–48). Even
though their mechanism of action is not completely
understood, several mechanisms have been suggested.
Most investigations propose different combinations of
DNA intercalation (49), topoisomerase inhibition (50),
DNA alkylation (51,52), and induction of reactive oxygen
species (ROS) (53) depending on the compound structural
features.
Many of the drugs clinically approved or still in
compounds (figure 7). The quinoid moiety is present in
anthracyclines which are among the most used anticancer
drugs ever developed (44). Daunorubicin (Cerubidine®)
and doxorubicin (Adriamycin®), the most prominent
members of this class of antitumor agents, are clinically
used in the therapy of solid cancers as well as
hematological malignancies (54). Likewise, mitoxantrone
(Novantrone®), a dihydroxyanthracenedione, is approved
for the treatment of certain types of neoplasms such as
metastatic breast cancer, acute myeloid leukemia, and non-
Hodgkin's lymphoma (55). Bioreductive alkylating agents
such as mitomycin C and its derivatives also display
remarkable antitumor effects. Mitomycin C, a potent DNA
crosslinker, is a FDA approved drug for the treatment of
solid tumors (56,57). Additionally, ß-lapachone, an ortho-
naphthoquinone, originally isolated from a tree, is also
being evaluated for its cancer growth inhibitory properties
in diverse tumors (44). Even though in many cases the
antitumor mechanisms remain uncertain, it is
unquestionable that the presence of the quinone moiety is
exceptionally remarkable in the development of new
anticancer drugs.