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The chromenopyrazole scaffold in the modulation of the endocannabinoid system: a broad therapeutic prospect
effects in vitro and in vivo. Its ability to selectively both types of prostate cancer would be a very good
decrease viability in cancer versus normal cells, along with challenge to move forward.
its striking antitumor capacity, open novel therapeutic
avenues for the exploitation of the chromenopyrazole The ECS is also deregulated on the course of this
moiety in cancer physiopathology. In view of these results, pathology. The expression of cannabinoid receptors has
chromenopyrazoledione 10 can be considered a new been studied in prostate cancer tissue. It was demonstrated
anticancer drug candidate offering hope for the treatment that CB1R expression is upregulated in these neoplasms
of TNBC. (85). Indeed, high CB1R immunoreactivity score in
prostate cancer tissue is associated with prostate cancer
4.2. Chromenopyrazolediones for Prostate cancer (PC) severity and outcome (86). Moreover, expression of
FAAH (87) and GPR55 (88) is demonstrated in some
Prostate cancer (PC) is the second most common prostate carcinoma cell lines. In line with these
cancer worldwide for Western men. The rates are observations, different endocannabinoids or cannabis-like
increasing in recent years since life expectancy is longer compounds were evaluated exhibiting their ability to
(80). Even though most prostate cancers grow slowly, inhibit prostate cancer cell proliferation and produce
aggressive cases are also diagnosed. These oncogenic cells apoptosis through cannabinoid receptor mechanisms (89).
may metastasize to other parts of the body such as bones The dysregulation of this system correlates with prostate
and lymph nodes (81). Therefore, there are extensive cancer grade and progression. Therefore, modulation of
ongoing efforts to develop new therapeutic strategies to the ECS may offer novel therapeutic avenues for prostate
treat prostate cancer (82). cancer as well (90,91).
The basis of medical treatment for advanced prostate Because of the aforementioned expression patterns in
cancer is androgen deprivation therapy (ADT), intended to prostate cancer, CB1R agonists should provide a new
lower testosterone levels. However, the reduction of therapeutic approach for this type of cancer. Therefore,
clinical symptoms and tumor growth is accompanied by among the series of chromenopyrazolediones previously
systemic consequences of testosterone deficiency such as described (figure 8), the para-quinone derivatives, which
osteoporosis, gynecomastia, anemia and insulin resistance bind to CB1R, were selected for their evaluation in prostate
among others (83,84). Androgen deprivation is associated cancer-derived cell lines (63).
with a gradual transition of prostate cancer cells through a
spectrum of androgen dependence, androgen sensitivity, Cell viability assays in androgen-dependent (LNCaP)
and ultimately androgen independence. Too often the and androgen-refractory (PC-3) prostate cancer cell lines
appearance of hormone refractory cancer cells eventually revealed that these cannabinoid-quinones exhibit
leads to the recurrence of cancer which turns to a antiproliferative effects with IC50s in the micromolar
hormone-independent state. This type of prostate cancer range. Compound 11 (figure 10), which is the most potent
has a more aggressive phenotype and is unresponsive to among the derivatives tested, displayed an IC50 of 15 µM
further hormonal therapy whereby prognosis is very poor. in both LNCaP and PC-3 prostate cancer cells.
Therefore, to find a treatment which could reduce or block
Figure 10. Cannabinoid receptor affinity and half-maximum inhibitory concentrations (IC50) in LNCaP and PC3 cancer cell
lines of para-chromenopyrazoledione 11.
Further analysis of chromenopyrazoledione 11 The results obtained for para-chromenopyrazoledione
indicated that it induces cell death through apoptosis, 11 validated the antiproliferative capacity of
being more efficient in the androgen-sensitive LNCaP cell chromenopyrazole-derived cannabinoid quinones, and
line. At a molecular mechanistic level, the cytotoxicity of therefore, the cannabinoid/ROS antitumor proof-of-
11 was shown to be mediated through CB1R, oxidative concept.
stress and modulation of the nuclear receptors PPAR?
(peroxisome proliferator-activated receptors) receptors 4.2a Porphyrin conjugate strategy
(63).
In the field of cancer therapy, strategies have been
In vivo studies of para-quinone 11 confirmed the explored during these last years in which porphyrins are
results obtained in vitro. Treatment with 11 at a dose of 2 conjugated to molecules showing preferential
mg/kg totally inhibited the growth of androgen-dependent accumulation for tumor tissues or having affinity for
prostate tumor xenografts in mice. receptors expressed in tumors (92).
Porphyrin derivatives constitute the central element of
@Real Academia Nacional de Farmacia. Spain 173
