The current state and future perspectives of cannabinoids in cancer biology. Śledziński P(1), Zeyland J(1), Słomski R(1)(2), Nowak A(1). The current state and future perspectives of cannabinoids in cancer . Nabilone ( THC synthetic analogue) is allowed for the treatment of. 1. Śledziński P, Zeyland J, Słomski R, Nowak A. The current state and future perspectives of cannabinoids in cancer biology. Cancer Med.
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Pre-clinical animal trials have revealed very promising data showing that cannabinoids can selectively kill tumor cells, leaving healthy cells unharmed in a variety of cancer types. However, any anti-tumor effects appear to be largely dependent on cancer cell type and the potency and ratio of the different cannabinoids, primarily THC and CBD.
It has become clear that cannabinoids can effectively alter the development of a cancer cells life cycle, from its formation, proliferation to its death. Integrating cannabis into clinical cancer care The current state and future perspectives of cannabinoids in cancer biology Cancer Anecdotal, preclinical, and clinical evidence attest to the broad protective role of our endocannabinoid system in preventing and suppressing chronic illnesses like cancer.
The health effects of cannabis and cannabinoids: The current state of evidence and recommendations for research. Cannabis might be less potent than other available antiemetics, but for some patients, it is the only agent that works, and it is the only antiemetic that also increases appetite.
Malignant pleural mesothelioma MPM is an aggressive and invariably fatal cancer of the pleural surface that is associated with asbestos exposure . MPM is usually detected at an advanced stage, therefore treatment options are limited to systemic chemotherapy with cisplatin and pemetrexed as the mainstay of palliative treatment for most patients .
Lung Cancer - February 7, Category: However, whether or not the effects of the program are long-lasting and if the program consequently changed physicians' practice with regard to lun Internal Medicine - February 6, Category: Intern Med Source Type: A Systematic Integrative Literature Review.
The disease unpredictability, the misconceptions about palliative care being only for people with cancer, and only relevant in the last days of life, prevent a timely integrated care plan. This systematic review aimed to explore how palliative care is provided in advanced COPD and to identify elements defining integrated palliative care. Eight databases, including M Potential reasons include at least the following: ST does not work; the sham treatment had some effect; small sample size with heterogeneous patients; misplaced electrodes on an area of nonpainful but damaged nerves; or a combination of these factors.
Analgesic, antiemetic, appetite stimulant, tumour growth inhibitor [ ]. Analgesic, antiemetic, appetite stimulant tumour growth inhibitor [ ]. Anti-tumor agent, inhibitors of mitochondrial O2 consumption in human sperm, antiemetic, appetite stimulant [ , - ]. Anti-tumor agent, attenuate catalepsy, immunosuppressive, inflammatory or anti-inflammatory agent depends upon used concentration of drug , antipsychotics [ - ]. Hepatic ischaemia, anti-inflammatory [ - ].
Anti-inflammatory [ ]. Analgesic, multiple sclerosis, neuroprotective [ ]. Anti-tumor,anti-inflammatory, antiemetic [ ]. Neurological disorders, Anti-cancer [ 83 , ]. Tumour growth inhibitor in glioma, skin carcinoma, lymphoma [ ].
Metabolic syndrome [ ]. Improves recognition loss induced by naloxone in morphine withdrawal mice, various pharmacological property [ - ]. Cannabinoids and their classification. This figure illustrates how cannabinoids are divided into three main categories according to their availability in nature. Endogenous cannabinoids which are produced in our body include lipid molecules containing long-chain polyunsaturated fatty acids, amides, esters and ethers that bind to CB1 or CB2 receptors.
Endocannabinoids mainly act as neuromodulators or retrograde messengers which affect the release of various neurotransmitters in the peripheral and neural tissues [ 14 ].
They also play important role in inflammation, insulin sensitivity, and fat and energy metabolism. Inhibition of endocannabinoids may be a tool in reducing the prevalence of metabolic syndrome [ 15 ]. Two of the best characterized endocannabinoids are N-arachidonoylethanolamine AEA-anandamide and 2- arachidonoylglycerol 2-AG which affect our mood, appetite, pain sensation, inflammation response, and memory [ 7 , 16 ].
Anandamide which was isolated from porcine brain in was shown as the first brain metabolite, to function as a ligand for CB1, [ 7 ]. Palmitoyl-ethanolamide, or N- 2-Hydroxyethyl hexadecamide N-acyl-ethanolamide is co-synthesized with anandamide in all tissues and acts through CB2 [ 18 - 20 ]. Another putative endogenous cannabinoid, oleamide, or cisoctadecenoamide, has also been isolated and shown to have similar actions to anandamide in the behavioral rodent tests [ 22 ].
Phytocannabinoids are only known to occur naturally in significant quantity in the cannabis plant, and are concentrated in a viscous resin that is produced in glandular structures known as trichomes. Synthetic cannabinoids have been extensively used as a pharmacological agent, both in vitro and in vivo , to obtain more detailed insight of cannabinoid action, in order to evaluate their potential clinical use.
They showed both antineoplastic and protumoral activity, depending on type of agonist, target tissues, route of administration, doses and duration of the treatment [ 26 - 27 ].
Synthetic cannabinoids are classified on the basis of chemical structure of molecules and they are capable of a more selective activation of cannabinoid receptor [ 28 ]. Compounds isolated from the plant C. The most psychotropic component of the C. Furthermore bi-cyclic analog, CP, an important cannabinoid agonist has similar affinity for CB1 and CB2 receptors. Also, it is highly potent in vivo. CP and CP are other cannabinoids that fall in this category. These are a family of aminoalkylindoles with cannabimimetic properties.
It exhibits high affinity for both cannabinoid receptors, but more selective for CB2. It has similar pharmacological effects like THC in vivo. Anandamide, which is an endogenous cannabinoid ligand was originally discovered in mammalian brain and other tissues and acts similar to THC.
These represent diarylpyrazole compounds which function antagonistic to cannabinoid receptors [ 34 ]. Cannabinoid mediated signaling in cancer cells. Cannabinoids activate CB1 or CB2 receptor which in turn modulates diverse signaling targets. Role of cannabinoid in different cancers and its associated signaling. Suppression of nerve growth factor Trk receptors and prolactin receptors. One of the important aspects of an effective anti-tumor drug is its ability to inhibit proliferation of cancer cells.
Cancer cells proliferate rapidly in uncontrolled manner. Also, these cells escape death mechanism which a normal cell undergoes like apoptosis. Apoptosis is a kind of programmed cell death PCD mechanism which involves activation of caspase dependent and independent pathways [ 39 ].
Cannabinoids have been proved to be anti-proliferative and apoptotic drugs. This section comprises of the detailed role of cannabinoids in modulation of tumor proliferation, cell cycle and apoptosis in various cancer types.
Breast cancer is one of the most common human malignancies and the second leading cause of cancer-related deaths in women, and its incidence in the developing world is on the rise [ 40 - 41 ].
It is mainly classified into three main subtypes according to their molecular profiles: Cannabinoid-based medicines have been useful for the treatment of these three breast cancer subtypes. But no correlation between CB1 expression and ErbB2 expression was found [ 44 ]. Cannabinoids modulate the growth of hormone sensitive breast cancer cells as shown in Fig.
Endocannabinoids such as anandamide AEA are important lipid ligands regulating cell proliferation, differentiation and apoptosis. Breast tumor cells express FAAH abundantly. Cell cycle arrest is responsible for apoptotic cell death. This effect is occurred by inhibition of the cyclin-dependent kinase CDK2 [ 50 , 60 ]. Modulatory effect of cannabinoids on hormone sensitive breast cancer cells. CBD enhances the interaction between beclin1 and Vps34; it inhibits the association between beclin1 and Bcl-2 [ 63 ].
Thus, cannabinoids along with COX-2 inhibitors or other chemotherapeutic agents may represent as novel chemopreventive tools for the treatment of breast cancer. Cannabinoids inhibit key signaling targets in triple negative breast cancer which has worse prognosis in patients. Prostate cancer is the most common malignancy among men of all races and is one of the leading causes of cancer death in this population. JWH triggered a de novo synthesis of ceramide, which induced cell death, followed by JNK c-Jun N-terminal kinase activation and Akt inhibition [ 76 ].
Interestingly, R -methanandamide was shown to have a mitogenic effect on LNCaP cells at very low doses [ 46 , 75 ]. A recent report showed that FAAH is also over-expressed in prostate cancer cells and the inhibition of FAAH can enhance the survival of cancer patient [ 80 - 81 ].
Lung cancer has one of the highest mortality rates among cancer -suffering patients. These results generate a rationale for further in vivo efficacy studies with this compound in preclinical cancer models. Melanoma is the mainly cause of skin cancer—related deaths worldwide. CB1 and CB2 receptors are expressed in normal skin and skin tumors of mice and humans [ 85 ]. C57 and HaCa4 and reduces malignant tumors in nude mice [ 85 ].
WIN, or JWH induced G1 cell cycle arrest on melanoma cells, via inhibition of p-Akt and hypophosphorylation of the pRb retinoblastoma protein tumor suppressor [ 85 ]. Pancreatic cancer is one of the most aggressive and devastating human malignancies. Cannabinoid receptors on pancreatic cancer cells may affect prognosis and pain status of PDAC patients [ 86 ]. Cannabinoid administration leads to apoptosis of pancreatic tumor cells via CB2 receptor and ceramide-dependent up-regulation of p8 and ATF-4 and TRB3 stress—related genes [ 87 ].
Chondrosarcoma and osteosarcoma are the most frequent primary bone cancers [ 89 ]. Bone metastases are a frequent complication of cancer and the most frequent type of pain related to cancer. Breast cancer and prostate cancer mainly metastasize to bone which act as a fertile soil for the growth of secondary tumors [ 90 ].
The skeletal endocannabinoid system plays a significant role in regulating bone mass and bone turnover. The expression levels of CB1 and CB2 receptors were analyzed in bone cancer patient using immunohistochemistry [ 91 ].
Bone metastatic patient has severe pain so cannabinoids can attenuate pain and hyperalgesia [ 92 ]. Sativex is the combination of deltatetra-hydrocannabinol and cannabidiol, used to treat pain in cancer [ 92 ].
Effects of subcutaneously administered WIN55, on weight bearing and mechanical hyperalgesia were consistent with cannabinoid receptor mediated anti-nociception [ 93 ].
WIN55, also attenuates tumour-evoked mechanical hyperalgesia following local intraplantar administration through activation of CB1 and CB2 receptors [ 95 ]. Injection of CP55 produced anti-nociceptive properties in the tail flick test and suppressed mechanical hyperalgesia in NCTC or melanoma BF10 xenografted bone tumor model [ 96 ].
Indeed, intraplantar administration of AEA reduces mechanical hyperalgesia, URB increases AEA levels and decreases hyperalgesia in a model of calcaneous bone cancer pain [ 91 ]. However, intrathecal administration of either URB or MGL URB inhibitors failed to produce anti-nociception when tested for spontaneous flinches, limb use and weight bearing [ 97 ]. Moreover, the CB1 agonist arachidonoylchloroethylamide ACEA produces anti—nociceptive properties following intrathecal administration in this model; ACEA suppressed spontaneous flinches and increased limb use and weight bearing [ 97 ].
AM produces significantly reduced bone loss and decreased the incidence of cancer -induced bone fractures [ 94 , 98 ]. Administration of JWH and AM attenuated tumor-evoked tactile allodynia and thermal hyperalgesia by reducing NR2B-dependent activity [ 98 - 99 ]. JWH increased survival without the major side effects of current therapeutic options. Gliomas are the most important group of malignant primary brain tumors and one of the most aggressive forms of cancer, exhibit high resistance to conventional chemotherapies.
CB2 expression levels were higher in glioblastoma tissues in comparison to CB1. Selective CB2 agonists may become important targets for the treatment of glioma. C annabinoids , inhibit tumor growth in animal models by inducing apoptosis of tumor cells and impairing tumor angiogenesis. The growth inhibitory effect of these cannabinoids is prevented by blocking ceramide synthesis, and the expression of the stress protein p8 [ - ].
The activation of this pathway was necessary for the antitumor action of cannabinoids in vivo [ ]. Glioma cells develop resistance to cannabinoid treatment due to the upregulation of Amphiregulin EGFR family ligand and the growth factor midkine Mdk [ - ].
Amphiregulin expression was associated with increased ERK activation and Mdk mediated its protective effect through ALK which interferes with autophagic cell death [ ].
The silencing of amphiregulin and Mdk or ALK pharmacological inhibition can overcome drug resistance of glioma to cannabinoids antitumoral action.
Furthermore, to improve the efficacy of cannabinoids action, microencapsulation methods were used which facilitates a sustained release of the two cannabinoids for several days [ ]. In contrast, cannabinoids decreased cell viability as assessed by metabolic activity. The persistent expression of mammalian homolog of Atg8 with microtubule-associated protein-1 light chain-3 II LC3 II and p62, as well as the lack of protection from chloroquine, indicates that lysosomal degradation is not involved in this cytoplasmic vacuolation process, distinguishing from classical autophagy [ ].
Paraptosis-like cell death-a third type of a programmed cell death occurred in response to cannabinoids [ ]. Oral cancer is mainly occurs in the mouth including lips, tongue and throat. Smoking, tobacco chewing and alcohol consumption increases the incidence of oral cancer. Radiation therapy and surgery is the common treatment for oral cancer.
Marijuana smoking increases the incidence of head and neck cancer in young people but its constituent, cannabinoids have anti-tumor properties. Thyroid carcinoma is the most aggressive form which occurs in thyroid gland. IL gene transfer in to anaplastic thyroid carcinoma cell line ARO has anti-tumorigenic effect [ ]. This effect was observed due to the activation of cannabinoid receptor.
Migration and invasion are characteristic features of cancer cells. Carcinoma cells that are invasive have higher migratory potential which helps them to disseminate into the surrounding tissues and spread to other organs, ultimately leading to metastasis [ ]. Angiogenesis, which involves growth of new vasculature has been shown to be closely related to cancer metastasis. Developing novel anti-invasive and anti-angiogenic targets would be more effective in inhibiting metastasis at earlier stage [ ].
In lung cancer, CBD inhibits invasion of A cells both in vitro and in vivo that was accompanied by up-regulation of tissue inhibitor of matrix metalloproteinase-1 TIMP-1 and decreased expression of plasminogen activator inhibitor-1 PAI-1 [ - ]. In skin cancer, treatment of WIN, or JWH caused impairment of tumor vascularization and decreased expression of proangiogenic factors such as VEGF, placental growth factor, and angiopoietin-2 [ 85 ].
In glioma, [ ], one study reveals that CBD also inhibits angiogenesis by modulating MMP-2 pathway and Id-1 gene expression in glioblastoma cells [ - ]. CBD inhibits cell proliferation and invasion of 4T1 cells mammary metastatic cell line and reduces primary tumor volume as well as lung metastasis in 4T1-xenografted orthotopic model of nude mice [ - ].
This anti-metastatic effect was mediated by downregulation of Id-1 a basic helix-loop-helix transcription factor inhibitor , ERK and also by inhibiting the ROS pathway.
Furthermore, CBD reduced the number of metastatic foci in 4T1- tail vein injected syngenic model. Cancer stem cells CSC are part of the tumor cell population. Though they might be very less in number, they have the ability to self renew and replicate to produce enormous cancer cell types.
The current state and future perspectives of cannabinoids in cancer biology.
The current state and future perspectives of cannabinoids in cancer biology. Article (PDF Available) in Cancer Medicine 7(Suppl 2) · February. The current state and future perspectives of cannabinoids in cancer biology. Paweł Śledziński, Joanna Zeyland, Ryszard Słomski, Agnieszka Nowak. Cancer . To date, cannabinoids have been allowed in the palliative medicine due to their The current state and future perspectives of cannabinoids in cancer biology.