Jacob Bell
New Member
MAURIZIO BIFULCO1 & VINCENZO DI MARZO2
After almost four millennia of more-orless
licit recreational and medicinal use
of Cannabis sativa, the nature of the
principle psychotropic constituent of
this renowned plant (—)-Δ9-tetrahydrocannabinol (THC), was
elucidated between the 1940s and 1960s (refs. 1,2). This breakthrough
eventually opened the way to the identification first
of the sites of action of THC, the cannabinoid CB1 and CB2 receptors3,
and subsequently of the endocannabinoids, endogenous
agonists of the cannabinoid receptors4. CB1 receptors are
expressed in several brain regions, with high concentrations
in the basal ganglia, hippocampus, cerebellum and cortex,
and mediate the typical psychotropic effects of Cannabis, marijuana
and THC. Lower, albeit functionally active, amounts of
CB1 receptors are also found in several peripheral tissues and
cell lines, whereas CB2 receptors are mostly confined to immune
tissues and cells and seem to underlie the immune-suppressant
actions of THC (ref. 4). Both CB1 and CB2 receptors
are expressed by cells from the early stages of fertilized oocyte
development5, and CB1 expression in the developing brain is
substantially different from that observed in the adult brain6.
These observations, together with the ubiquity of the endocannabinoids
anandamide and 2-arachidonoylglycerol (2-AG)
in both vertebrate and invertebrate tissues, and their modulatory
activity on proteins and nuclear factors involved in cell
proliferation, differentiation and apoptosis, suggest that the
endocannabinoid signaling system might be involved in the
control of cell survival, transformation or death7.
The anti-neoplastic activity of THC and its analogs was first
observed in the early 1970s (ref. 8), before the discovery of
cannabinoid receptors and endocannabinoids. Surprisingly,
although these observations were of potential interest, no indepth
investigations were performed on this topic at the time.
This contrasts with the investigation of the therapeutic effects
of cannabinoids on some cancer-related disorders, such as
emesis and nausea. Indeed, the only therapeutic uses for
which oral THC (Dronabinol, Marinol) and its synthetic derivative
nabilone (Cesamet) have received regulatory approval in
the United States are the alleviation of nausea and emesis for
cancer patients undergoing chemotherapy and the stimulation
of appetite for patients with AIDS. Although the clinical
efficacy of these palliative effects of THC is now being debated9,10,
recent studies have revisited the possibility that
drugs targeting the endogenous cannabinoid system might
also be used to retard or block cancer growth.
Cannabinoids and solid tumor growth
Based on the immunosuppressive effects of Cannabis, studies
were originally performed in animals to investigate the possibility
that marijuana smoking, or long-term THC treatment,
might favor tumor growth. These studies, however, produced
contradictory results. For example, the data of one study suggested
that the growth of a lung carcinoma
was enhanced11, whereas in a twoyear
chronic administration study with
high THC doses, a reduction of the
spontaneous onset of hormone-dependent tumors occurred12.
Another in vivo study demonstrated that both marijuana and
placebo smoke result in the suppression of the growth of sarcoma
180 tumors13. A parsimonious interpretation of these investigations
is that, although some pro-tumor effects of THC
are due to CB2 receptor—mediated immune suppression11, marijuana
smoke, like tobacco or cocaine smoke, might favor the
onset of lung cancer by causing bronchial epithelium damage14.
Other experiments have been undertaken to determine the
effect of endogenous cannabinoid receptor ligands on cancer
cells in vitro. It was found that 4—5-day treatment of human
breast cancer cell (HBCC) lines with sub-micromolar concentrations
of endocannabinoids results in complete blockade of
cell proliferation15. This effect is mediated by the CB1 receptor
subtype and is due to inhibition of the action of endogenous
prolactin, which HBCCs in culture use as an autocrine growth
factor. In fact, anandamide inhibits the expression of prolactin
receptors in these cells15, and agents activating the CB1
receptor, via the same mechanism, also counteract the proliferation
of human prostate cancer cells induced by exogenous
prolactin16. Indeed, both human breast and prostate cancer
cells were shown to express high levels of CB1 receptors that
had never been detected previously in the corresponding
healthy tissues. HBCCs also respond to the nerve growth factor
(NGF) by proliferating more rapidly, and two-day treatment
of HBCCs with CB1 receptor agonists suppresses the
levels of trk proteins, the receptors for NGF, thereby resulting
in the inhibition of NGF-induced proliferation16. Thus, endocannabinoids
seem to act as selective inhibitors of growth factor—
dependent breast and prostate cancer-cell proliferation
(Fig. 1). It is possible that, by interfering with the expression of
other growth and mitogenic factors, substances that activate
CB1 receptors might also exert more general anti-tumor as well
as anti-angiogenic effects.
Inhibition of proliferation, however, is not the only mechanism
through which cannabinoid receptor agonists block
solid tumor growth in vitro (Table 1, Fig. 1). THC was found to
induce apoptosis of glioma and prostate cancer cells, even
though the involvement of cannabinoid receptors in these
early studies was unclear17,18; more recently, a similar effect by
anandamide was suggested to be mediated by another controversial
target for this compound, the vanilloid VR1 receptor19,20.
Most of the compounds that inhibit the growth of cancer
cells in vitro turn out to be disappointingly ineffective when
tested in animals. However, there is now evidence that substances
that activate cannabinoid receptors may act as anti-neoplastic drugs in vivo. Intratumoral THC administration can
effectively reduce the growth of gliomas in mice by inducing
apoptosis of the tumor cells. This effect is attenuated by a
combination of cannabinoid CB1 and CB2 receptor antagonists21.
More recently, it was reported that selective activation
of the cannabinoid CB2 receptor results in a striking inhibition
of glioma growth in vivo, and that CB2 receptor expression correlates
with the level of malignancy in astrocytomas22. These
studies, which relate to a type of malignant tumor for which a
successful treatment has yet to be developed, have resulted recently
in the unprecedented decision by the Spanish government
to allow a clinical study aimed at investigating the effect
of intra-tumoral THC administration on glioma in humans.
Repeated intra-tumoral administration of a low, non-psychotropic
dose of a metabolically stable anandamide analog,
met-fluoro-anandamide, inhibits the growth of tumors induced
in nude mice by injection of rat thyroid epithelial FRTL-
5 cells transformed into cancer cells by the oncogene K-ras23.
This anti-tumor effect is almost entirely erased by a selective
antagonist of CB1 receptors, which, accordingly, are found in
tumors derived from transformed thyroid cells. Moreover, this
effect is accompanied by a strong reduction of the activity of
the K-ras oncogene protein product, p21ras, and is due, as in
the case of HBCCs (ref. 15), to blockade of the cell cycle prior
to the entry into the DNA synthetic (S) phase. So, once again,
interference with a mitogenic signal underlies a cytostatic action
by a cannabinoid CB1 receptor agonist (Fig. 1). It was also
shown that the expression of CB1 receptors is oppositely regulated
in healthy and transformed thyroid cells (as well as in tumors
derived from these latter cells) following treatment with
met-fluoro-anandamide, and is suppressed or enhanced in
healthy or cancer cells, respectively.
Thus, the degree of CB1 receptor expression
determines the extent of the responsiveness
of normal or transformed
FRTL-5 cells to (endo)cannabinoids23.
The enhancement of cannabinoid receptor
expression in malignant versus
healthy tissues, observed so far in
gliomas and transformed thyroid
cells22,23, might suggest a possible role of
the endocannabinoid system in the
tonic suppression of cancer growth.
However, other than the finding of alterations
of anandamide and/or 2-AG
levels in some tumors as compared with
the corresponding healthy tissues24,25,
no evidence has been reported thus far
to support this hypothesis.
Progress has been made instead towards
the understanding of the intracellular
events underlying the in vitro and
in vivo anti-tumor effects of cannabinoid
receptor agonists. It is now established
that THC and endocannabinoids
stimulate the activity of proteins that
are downstream of the activation of
p21ras, that is, the mitogen-activated
protein kinases (MAPKs)7. In HBCCs, inhibition
of extracellular signal-regulated
kinase (ERK), a particular class of
MAPKs, counteracts the effects of anandamide
on cell proliferation and on prolactin and NGF receptor
expression26. The apoptotic effect of THC on glioma cells
seems to be mediated by sustained ceramide synthesis and
ERK-dependent pathways21,22. Hence, it is possible that by
modulating the activity of both p21ras and MAPKs, the
cannabinoid receptors regulate the fate of cancer cells (for example,
apoptosis or cessation of proliferation) (Fig. 1).
Can cancer therapies target the endocannabinoid system?
The findings discussed here, in our opinion, should prompt
further studies on the therapeutic potential in cancer treatment
of substances that modulate the activity of cannabinoid
receptors or the levels of endocannabinoids, particularly as
other possible targets for the anticancer action of these compounds,
such as metastasis and angiogenesis, are still largely
unexplored. Cannabinoids appear to be well tolerated in animal
studies and do not produce the generalized toxic effects in
normal tissues that limit most conventional agents used in
chemotherapy. However, together with obvious social, political
and legal considerations, the therapeutic application of agonists
selective for CB1 receptors, as in treatments for breast
and thyroid cancer, should be weighed against the undesired
psychotropic side effects expected from the stimulation of
these receptors in the brain. Although the activation of 'central'
CB1 receptors has been and still is currently exploited to
alleviate two typical symptoms of cancer patients under
chemotherapy, that is, lack of appetite and nausea, other psychotropic
effects that are likely to follow from chronic treatment
with cannabinoids, such as attentional dysfunction and
impairment of cognitive and psychomotor performance27,
might be poorly tolerated. Furthermore, the potential for addiction and tolerance to psychoactive cannabinoids after prolonged
use has not been yet fully assessed. On the other hand,
the administration of compounds selective for the CB2 receptor,
as in the treatment of gliomas, would be devoid of psychotropic
effects but might cause the immune-suppressive
effects typical of plant cannabinoids, which seem to be mediated
mostly by this receptor subtype and, at least in one case,
have been reported to counteract the immune defense against
tumor growth11.
In those scenarios where effectiveness against cancer-cell
growth were to be conclusively proven in vivo, the side effects
of CB1-selective agonists might be overcome, at least in principle,
by using one or a combination of the following strategies
also listed in Table 1: 1) intra-tumoral application of cannabinoids
seems to result in little, if any, undesired 'central' effects
in mice21—23, although its safety and efficacy in humans still
needs to be assessed; 2) the use of these substances in combination
with non-psychotropic 'entourage' compounds, which
lower the threshold of concentrations necessary to observe
CB1 receptor-mediated tumor suppressing effects in vitro28,29,
should also be investigated in vivo; 3) partial agonists of
cannabinoid receptors that are also capable of activating
vanilloid receptors, such as the synthetic compound arvanil30,
inhibit cancer-cell growth in vitro more potently and efficaciously
than 'pure' agonists of either receptor type20,30 (these
compounds are likely to have a lower addictive potential than
full agonists of CB1 receptors, and might be used as templates
for the development of new, potent multi-target anticancer
agents to be tested in vivo); and 4) CB1 receptor agonists that
do not cross the blood—brain barrier (BBB) should be developed
and evaluated against cancer cell growth.
Future research should also address the question of whether
or not endogenous cannabinoids exert tumor-suppressing effects,
as such a discovery might result in another approach for
the development of possibly harmless anti-cancer drugs. In
fact, selective inhibitors of endocannabinoid degradation with
no direct action on CB1 receptors, even if administered systemically,
would exhibit little if any psychotropic activity and
be most effective only in those tissues where the levels of endocannabinoids
are pathologically altered.
In conclusion, only further efforts towards the full assessment
of the effects of substances selectively targeting the endocannabinoid
system will provide the answer as to whether
these compounds might be exploited successfully as novel anticancer
agents. The recent findings discussed here indicate
that more basic and clinical research is needed not only to understand
if cannabinoids are as effective and safe as other therapeutic
drugs in the palliative care of cancer9,10, but also if they
can be used to retard tumor growth and spreading instead of,
or in addition to, conventional chemotherapy agents.
References
1. Adams, R. Marihuana. Harvey Lectures Ser. 37, 168—197 (1942).
2. Gaoni, Y. & Mechoulam R. Isolation, structure and partial synthesis of an active
constituent of hashish. J. Amer. Chem. Soc. 86, 1646 (1964).
3. Pertwee, R.G. Pharmacology of cannabinoid CB1 and CB2 receptors. Pharmacol.
Ther. 74, 129—180 (1997).
4. Di Marzo, V. 'Endocannabinoids' and other fatty acid derivatives with
cannabimimetic properties: Biochemistry and possible physiopathological relevance.
Biochim. Biophys. Acta. 1392, 153—175 (1998).
5. Paria, B.C., Das, S.K. & Dey, S.K. The preimplantation mouse embryo is a target
for cannabinoid ligand-receptor signaling. Proc. Natl. Acad. Sci. USA 92,
9460—9464 (1995).
6. Berrendero, F., Sepe, N., Ramos, J.A., Di Marzo, V. & Fernandez-Ruiz, J.J.
Analysis of cannabinoid receptor binding and mRNA expression and endogenous
cannabinoid contents in the developing rat brain during late gestation and
early postnatal period. Synapse 33, 181—191 (1999).
7. Guzman, M., Sanchez, C. & Galve-Roperh, I. Control of the cell survival/death
decision by cannabinoids. J. Mol. Med. 78, 613—625 (2001).
8. Munson, A.E., Harris, L.S., Friedman, M.A., Dewey, W.L.& Carchman, R.A.
Antineoplastic activity of cannabinoids. J. Natl. Cancer Inst. 55, 597—602 (1975).
9. Tramer, M.R. et al. Cannabinoids for control of chemotherapy induced nausea
and vomiting: Quantitative systematic review. Brit. Med. J. 323, 16—21 (2001).
10. Kinzbrunner, B.M. Review: Cannabinoids control chemotherapy-induced nausea
and vomiting but increase the risk for side effects. ACP J. Club 136, 19
(2002).
11. Zhu, L.X. et al. Δ-9-tetrahydrocannabinol inhibits antitumor immunity by a CB2
receptor-mediated, cytokine-dependent pathway. J. Immunol. 165, 373—380
(2000).
12. Toxicology and carcinogenesis studies of 1-trans-Δ-9-tetrahydrocannabinol in
F344N/N rats and BC63F1 mice. National Institutes of Health National
Toxicology Program, NIH Publication No. 97-3362 (November 1996).
13. Watson, E.S. The effect of marijuana smoke exposure on murine sarcoma 180
survival in Fisher rats. Immunopharmacol. Immunotoxicol. 11, 211—222 (1989).
14. Barsky, S.H., Roth, M.D., Kleerup, E.C., Simmons, M. & Tashkin, D.P.
Histopathologic and molecular alterations in bronchial epithelium in habitual
smokers of marijuana, cocaine, and/or tobacco. J. Natl. Cancer Inst. 90,
1198—1205 (1998).
15. De Petrocellis, L. et al. The endogenous cannabinoid anandamide inhibits
human breast cancer cell proliferation. Proc. Natl. Acad. Sci. USA 95, 8375—8380
(1998).
16. Melck, D. et al. Suppression of nerve growth factor Trk receptors and prolactin
receptors by endocannabinoids leads to inhibition of human breast and prostate
cancer cell proliferation. Endocrinology 141, 118—126 (2000).
17. Sanchez, C., Galve-Roperh, I., Canova, C., Brachet, P. & Guzman, M. Δ9-
tetrahydrocannabinol induces apoptosis in C6 glioma cells. FEBS Lett. 436, 6—10
(1998).
18. Ruiz, L., Miguel, A. & Diaz-Laviada, I. Δ9-tetrahydrocannabinol induces apoptosis in human prostate PC-3 cells via a receptor-independent mechanism. FEBS
Lett. 458, 400—404 (1999).
19. Maccarrone, M., Lorenzon, T., Bari, M., Melino, G. & Finazzi-Agrò, A.
Anandamide induces apoptosis in human cells via vanilloid receptors. Evidence
for a protective role of cannabinoid receptors. J. Biol. Chem. 275, 31938—31945
(2000).
20. Jacobsson, S.O.P., Wallin, T. & Fowler, C.J. Inhibition of rat C6 glioma cell proliferation
by endogenous and synthetic cannabinoids. Relative involvement of
cannabinoid and vanilloid receptors. J. Pharmacol. Exp. Ther. 299, 951—959
(2001).
21. Galve-Roperh, I. et al. Anti-tumoral action of cannabinoids: Involvement of sustained
ceramide accumulation and extracellular signal-regulated kinase activation.
Nature Med. 6, 313—319 (2000).
22. Sanchez, C. et al. Inhibition of glioma growth in vivo by selective activation of
the CB(2) cannabinoid receptor. Cancer. Res. 61, 5784—5789 (2001).
23. Bifulco, M. et al. Control by the endogenous cannabinoid system of ras oncogene-
dependent tumor growth. FASEB J. 15, 2745—2747 (2001).
24. Pagotto, U. et al. Normal human pituitary gland and pituitary adenomas express
cannabinoid receptor type 1 and synthesize endogenous cannabinoids: First evidence
for a direct role of cannabinoids on hormone modulation at the human
pituitary level. J. Clin. Endocrinol. Metab. 86, 2687—2696 (2001).
25. Maccarrone, M., Attina, M., Cartoni, A., Bari, M. & Finazzi-Agro, A. Gas chromatography-
mass spectrometry analysis of endogenous cannabinoids in healthy
and tumoral human brain and human cells in culture. J. Neurochem. 76,
594—601 (2001).
26. Melck, D. et al. Involvement of the cAMP/protein kinase A pathway and of mitogen-
activated protein kinase in the anti-proliferative effects of anandamide in
human breast cancer cells. FEBS Lett. 463, 235—240 (1999).
27. Hollister, L.E. Health aspects of cannabis: Revisited. Int. J.
Neuropsychopharmacol. 1, 71—80 (1998).
28. Bisogno, T. et al. Biosynthesis and degradation of bioactive fatty acid amides in
human breast cancer and rat pheochromocytoma cells–implications for cell
proliferation and differentiation. Eur. J. Biochem. 254, 634—642 (1998).
29. Di Marzo, V. et al. Palmitoylethanolamide inhibits the expression of fatty acid
amide hydrolase and enhances the anti-proliferative effect of anandamide in
human breast cancer cells. Biochem. J. 358, 249—255 (2001).
30. Melck, D. et al. Unsaturated long-chain N-acyl-vanillyl-amides (N-AVAMs):
Vanilloid receptor ligands that inhibit anandamide-facilitated transport and bind
to CB1 cannabinoid receptors. Biochem. Biophys. Res. Commun. 262, 275—284
(1999).
Source: Targeting The Endocannabinoid System In Cancer Therapy: A Call For Further Research
After almost four millennia of more-orless
licit recreational and medicinal use
of Cannabis sativa, the nature of the
principle psychotropic constituent of
this renowned plant (—)-Δ9-tetrahydrocannabinol (THC), was
elucidated between the 1940s and 1960s (refs. 1,2). This breakthrough
eventually opened the way to the identification first
of the sites of action of THC, the cannabinoid CB1 and CB2 receptors3,
and subsequently of the endocannabinoids, endogenous
agonists of the cannabinoid receptors4. CB1 receptors are
expressed in several brain regions, with high concentrations
in the basal ganglia, hippocampus, cerebellum and cortex,
and mediate the typical psychotropic effects of Cannabis, marijuana
and THC. Lower, albeit functionally active, amounts of
CB1 receptors are also found in several peripheral tissues and
cell lines, whereas CB2 receptors are mostly confined to immune
tissues and cells and seem to underlie the immune-suppressant
actions of THC (ref. 4). Both CB1 and CB2 receptors
are expressed by cells from the early stages of fertilized oocyte
development5, and CB1 expression in the developing brain is
substantially different from that observed in the adult brain6.
These observations, together with the ubiquity of the endocannabinoids
anandamide and 2-arachidonoylglycerol (2-AG)
in both vertebrate and invertebrate tissues, and their modulatory
activity on proteins and nuclear factors involved in cell
proliferation, differentiation and apoptosis, suggest that the
endocannabinoid signaling system might be involved in the
control of cell survival, transformation or death7.
The anti-neoplastic activity of THC and its analogs was first
observed in the early 1970s (ref. 8), before the discovery of
cannabinoid receptors and endocannabinoids. Surprisingly,
although these observations were of potential interest, no indepth
investigations were performed on this topic at the time.
This contrasts with the investigation of the therapeutic effects
of cannabinoids on some cancer-related disorders, such as
emesis and nausea. Indeed, the only therapeutic uses for
which oral THC (Dronabinol, Marinol) and its synthetic derivative
nabilone (Cesamet) have received regulatory approval in
the United States are the alleviation of nausea and emesis for
cancer patients undergoing chemotherapy and the stimulation
of appetite for patients with AIDS. Although the clinical
efficacy of these palliative effects of THC is now being debated9,10,
recent studies have revisited the possibility that
drugs targeting the endogenous cannabinoid system might
also be used to retard or block cancer growth.
Cannabinoids and solid tumor growth
Based on the immunosuppressive effects of Cannabis, studies
were originally performed in animals to investigate the possibility
that marijuana smoking, or long-term THC treatment,
might favor tumor growth. These studies, however, produced
contradictory results. For example, the data of one study suggested
that the growth of a lung carcinoma
was enhanced11, whereas in a twoyear
chronic administration study with
high THC doses, a reduction of the
spontaneous onset of hormone-dependent tumors occurred12.
Another in vivo study demonstrated that both marijuana and
placebo smoke result in the suppression of the growth of sarcoma
180 tumors13. A parsimonious interpretation of these investigations
is that, although some pro-tumor effects of THC
are due to CB2 receptor—mediated immune suppression11, marijuana
smoke, like tobacco or cocaine smoke, might favor the
onset of lung cancer by causing bronchial epithelium damage14.
Other experiments have been undertaken to determine the
effect of endogenous cannabinoid receptor ligands on cancer
cells in vitro. It was found that 4—5-day treatment of human
breast cancer cell (HBCC) lines with sub-micromolar concentrations
of endocannabinoids results in complete blockade of
cell proliferation15. This effect is mediated by the CB1 receptor
subtype and is due to inhibition of the action of endogenous
prolactin, which HBCCs in culture use as an autocrine growth
factor. In fact, anandamide inhibits the expression of prolactin
receptors in these cells15, and agents activating the CB1
receptor, via the same mechanism, also counteract the proliferation
of human prostate cancer cells induced by exogenous
prolactin16. Indeed, both human breast and prostate cancer
cells were shown to express high levels of CB1 receptors that
had never been detected previously in the corresponding
healthy tissues. HBCCs also respond to the nerve growth factor
(NGF) by proliferating more rapidly, and two-day treatment
of HBCCs with CB1 receptor agonists suppresses the
levels of trk proteins, the receptors for NGF, thereby resulting
in the inhibition of NGF-induced proliferation16. Thus, endocannabinoids
seem to act as selective inhibitors of growth factor—
dependent breast and prostate cancer-cell proliferation
(Fig. 1). It is possible that, by interfering with the expression of
other growth and mitogenic factors, substances that activate
CB1 receptors might also exert more general anti-tumor as well
as anti-angiogenic effects.
Inhibition of proliferation, however, is not the only mechanism
through which cannabinoid receptor agonists block
solid tumor growth in vitro (Table 1, Fig. 1). THC was found to
induce apoptosis of glioma and prostate cancer cells, even
though the involvement of cannabinoid receptors in these
early studies was unclear17,18; more recently, a similar effect by
anandamide was suggested to be mediated by another controversial
target for this compound, the vanilloid VR1 receptor19,20.
Most of the compounds that inhibit the growth of cancer
cells in vitro turn out to be disappointingly ineffective when
tested in animals. However, there is now evidence that substances
that activate cannabinoid receptors may act as anti-neoplastic drugs in vivo. Intratumoral THC administration can
effectively reduce the growth of gliomas in mice by inducing
apoptosis of the tumor cells. This effect is attenuated by a
combination of cannabinoid CB1 and CB2 receptor antagonists21.
More recently, it was reported that selective activation
of the cannabinoid CB2 receptor results in a striking inhibition
of glioma growth in vivo, and that CB2 receptor expression correlates
with the level of malignancy in astrocytomas22. These
studies, which relate to a type of malignant tumor for which a
successful treatment has yet to be developed, have resulted recently
in the unprecedented decision by the Spanish government
to allow a clinical study aimed at investigating the effect
of intra-tumoral THC administration on glioma in humans.
Repeated intra-tumoral administration of a low, non-psychotropic
dose of a metabolically stable anandamide analog,
met-fluoro-anandamide, inhibits the growth of tumors induced
in nude mice by injection of rat thyroid epithelial FRTL-
5 cells transformed into cancer cells by the oncogene K-ras23.
This anti-tumor effect is almost entirely erased by a selective
antagonist of CB1 receptors, which, accordingly, are found in
tumors derived from transformed thyroid cells. Moreover, this
effect is accompanied by a strong reduction of the activity of
the K-ras oncogene protein product, p21ras, and is due, as in
the case of HBCCs (ref. 15), to blockade of the cell cycle prior
to the entry into the DNA synthetic (S) phase. So, once again,
interference with a mitogenic signal underlies a cytostatic action
by a cannabinoid CB1 receptor agonist (Fig. 1). It was also
shown that the expression of CB1 receptors is oppositely regulated
in healthy and transformed thyroid cells (as well as in tumors
derived from these latter cells) following treatment with
met-fluoro-anandamide, and is suppressed or enhanced in
healthy or cancer cells, respectively.
Thus, the degree of CB1 receptor expression
determines the extent of the responsiveness
of normal or transformed
FRTL-5 cells to (endo)cannabinoids23.
The enhancement of cannabinoid receptor
expression in malignant versus
healthy tissues, observed so far in
gliomas and transformed thyroid
cells22,23, might suggest a possible role of
the endocannabinoid system in the
tonic suppression of cancer growth.
However, other than the finding of alterations
of anandamide and/or 2-AG
levels in some tumors as compared with
the corresponding healthy tissues24,25,
no evidence has been reported thus far
to support this hypothesis.
Progress has been made instead towards
the understanding of the intracellular
events underlying the in vitro and
in vivo anti-tumor effects of cannabinoid
receptor agonists. It is now established
that THC and endocannabinoids
stimulate the activity of proteins that
are downstream of the activation of
p21ras, that is, the mitogen-activated
protein kinases (MAPKs)7. In HBCCs, inhibition
of extracellular signal-regulated
kinase (ERK), a particular class of
MAPKs, counteracts the effects of anandamide
on cell proliferation and on prolactin and NGF receptor
expression26. The apoptotic effect of THC on glioma cells
seems to be mediated by sustained ceramide synthesis and
ERK-dependent pathways21,22. Hence, it is possible that by
modulating the activity of both p21ras and MAPKs, the
cannabinoid receptors regulate the fate of cancer cells (for example,
apoptosis or cessation of proliferation) (Fig. 1).
Can cancer therapies target the endocannabinoid system?
The findings discussed here, in our opinion, should prompt
further studies on the therapeutic potential in cancer treatment
of substances that modulate the activity of cannabinoid
receptors or the levels of endocannabinoids, particularly as
other possible targets for the anticancer action of these compounds,
such as metastasis and angiogenesis, are still largely
unexplored. Cannabinoids appear to be well tolerated in animal
studies and do not produce the generalized toxic effects in
normal tissues that limit most conventional agents used in
chemotherapy. However, together with obvious social, political
and legal considerations, the therapeutic application of agonists
selective for CB1 receptors, as in treatments for breast
and thyroid cancer, should be weighed against the undesired
psychotropic side effects expected from the stimulation of
these receptors in the brain. Although the activation of 'central'
CB1 receptors has been and still is currently exploited to
alleviate two typical symptoms of cancer patients under
chemotherapy, that is, lack of appetite and nausea, other psychotropic
effects that are likely to follow from chronic treatment
with cannabinoids, such as attentional dysfunction and
impairment of cognitive and psychomotor performance27,
might be poorly tolerated. Furthermore, the potential for addiction and tolerance to psychoactive cannabinoids after prolonged
use has not been yet fully assessed. On the other hand,
the administration of compounds selective for the CB2 receptor,
as in the treatment of gliomas, would be devoid of psychotropic
effects but might cause the immune-suppressive
effects typical of plant cannabinoids, which seem to be mediated
mostly by this receptor subtype and, at least in one case,
have been reported to counteract the immune defense against
tumor growth11.
In those scenarios where effectiveness against cancer-cell
growth were to be conclusively proven in vivo, the side effects
of CB1-selective agonists might be overcome, at least in principle,
by using one or a combination of the following strategies
also listed in Table 1: 1) intra-tumoral application of cannabinoids
seems to result in little, if any, undesired 'central' effects
in mice21—23, although its safety and efficacy in humans still
needs to be assessed; 2) the use of these substances in combination
with non-psychotropic 'entourage' compounds, which
lower the threshold of concentrations necessary to observe
CB1 receptor-mediated tumor suppressing effects in vitro28,29,
should also be investigated in vivo; 3) partial agonists of
cannabinoid receptors that are also capable of activating
vanilloid receptors, such as the synthetic compound arvanil30,
inhibit cancer-cell growth in vitro more potently and efficaciously
than 'pure' agonists of either receptor type20,30 (these
compounds are likely to have a lower addictive potential than
full agonists of CB1 receptors, and might be used as templates
for the development of new, potent multi-target anticancer
agents to be tested in vivo); and 4) CB1 receptor agonists that
do not cross the blood—brain barrier (BBB) should be developed
and evaluated against cancer cell growth.
Future research should also address the question of whether
or not endogenous cannabinoids exert tumor-suppressing effects,
as such a discovery might result in another approach for
the development of possibly harmless anti-cancer drugs. In
fact, selective inhibitors of endocannabinoid degradation with
no direct action on CB1 receptors, even if administered systemically,
would exhibit little if any psychotropic activity and
be most effective only in those tissues where the levels of endocannabinoids
are pathologically altered.
In conclusion, only further efforts towards the full assessment
of the effects of substances selectively targeting the endocannabinoid
system will provide the answer as to whether
these compounds might be exploited successfully as novel anticancer
agents. The recent findings discussed here indicate
that more basic and clinical research is needed not only to understand
if cannabinoids are as effective and safe as other therapeutic
drugs in the palliative care of cancer9,10, but also if they
can be used to retard tumor growth and spreading instead of,
or in addition to, conventional chemotherapy agents.
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Source: Targeting The Endocannabinoid System In Cancer Therapy: A Call For Further Research
