“Several studies demonstrated that cannabinoids reduce tumor growth, inhibit angiogenesis, and decrease cancer cell migration. As these molecules are well tolerated, it would be interesting to investigate the potential benefit of newly synthesized compounds, binding cannabinoid receptors (CBRs).

In this study, we describe the synthesis and biological effect of 2-oxo-1,8-naphthyridine-3-carboxamide derivative LV50, a new compound with high CB2 receptor (CB2R) affinity. We demonstrated that it decreases viability of Jurkat leukemia cells, evaluated by Trypan Blue and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), but mainly induces a proapoptotic effect. We observed an increase of a hypodiploid peak by propidium iodide staining and changes in nuclear morphology by Hoechst 33258. These data were confirmed by a significant increase of Annexin V staining, cleavage of the nuclear enzyme poly(ADP-ribose)-polymerase (PARP), and caspases activation. In addition, in order to exclude that LV50 non-specifically triggers death of all normal leukocytes, we tested the new compound on normal peripheral blood lymphocytes, excluding the idea of general cytotoxicity. To characterize the involvement of CB2R in the anti-proliferative and proapoptotic effect of LV50, cells were pretreated with a specific CB2R antagonist and the obtained data showed reverse results.

Thus, we suggest a link between inhibition of cell survival and proapoptotic activity of the new compound that elicits this effect as selective CB2R agonist.”

https://www.ncbi.nlm.nih.gov/pubmed/29973514

http://www.mdpi.com/1422-0067/19/7/1958

“Chemotherapy-induced peripheral neuropathy (CIPN) is a severe and dose-limiting side effect of cancer treatment that affects millions of cancer survivors throughout the world and current treatment options are extremely limited by their side effects.

Cannabinoids are highly effective in suppressing pain symptoms of chemotherapy-induced and other peripheral neuropathies but their widespread use is limited by central nervous system (CNS)-mediated side effects.

Here, we tested one compound from a series of recently developed synthetic peripherally restricted cannabinoids (PRCBs) in a rat model of cisplatin-induced peripheral neuropathy.

Our results demonstrate that PRCBs exemplified by PrNMI may represent a viable option for the treatment of CIPN pain symptoms.”

https://www.ncbi.nlm.nih.gov/pubmed/29981335

https://www.sciencedirect.com/science/article/pii/S0028390818303575?via%3Dihub

“Studies have emphasized an antineoplastic effect of the non-psychoactive, phyto-cannabinoid, Cannabidiol (CBD). However, the molecular mechanism underlying its antitumor activity is not fully elucidated.

Herein, we have examined the effect of CBD on two different human breast cancer cell lines: the ER-positive, well differentiated, T-47D and the triple negative, poor differentiated, MDA-MB-231 cells.

In both cell lines, CBD inhibited cell survival and induced apoptosis in a dose dependent manner as observed by MTT assay, morphological changes, DNA fragmentation and ELISA apoptosis assay. CBD-induced apoptosis was accompanied by down-regulation of mTOR, cyclin D1 and up-regulation and localization of PPARγ protein expression in the nuclei and cytoplasmic of the tested cells.

The results suggest that CBD treatment induces an interplay among PPARγ, mTOR and cyclin D1 in favor of apoptosis induction in both ER-positive and triple negative breast cancer cells, proposing CBD as a useful treatment for different breast cancer subtypes.”

“The endocannabinoid system has emerged as a considerable target for the treatment of diverse diseases.

In addition to the well-established palliative effects of cannabinoids in cancer therapy, phytocannabinoids, synthetic cannabinoid compounds as well as inhibitors of endocannabinoid degradation have attracted attention as possible systemic anticancer drugs.

As a matter of fact, accumulating data from preclinical studies suggest cannabinoids elicit effects on different levels of cancer progression, comprising inhibition of proliferation, neovascularisation, invasion and chemoresistance, induction of apoptosis and autophagy as well as enhancement of tumour immune surveillance.

Although the clinical use of cannabinoid receptor ligands is limited by their psychoactivity, nonpsychoactive compounds, such as cannabidiol, have gained attention due to preclinically established anticancer properties and a favourable risk-to-benefit profile.

Thus, cannabinoids may complement the currently used collection of chemotherapeutics, as a broadly diversified option for cancer treatment, while counteracting some of their severe side effects.”

“The psychoactive properties of cannabinoids are well known and there has been a continuous controversy regarding the usage of these compounds for therapeutic purposes all over the world. Their use for medical and research purposes are restricted in various countries. However, their utility as medications should not be overshadowed by their negative physiological activities.

This review article is focused on the therapeutic potential and applications of phytocannabinoids and endocannabinoids. It highlights their mode of action, overall effects on physiology, various in vitro and in vivo studies that have been done so far and the extent to which these compounds can be useful in different disease conditions such as cancer, Alzheimer’s disease, multiple sclerosis, pain, inflammation, glaucoma and many others.

Thus, this work is an attempt to make the readers understand the positive implications of these compounds and indicates the significant developments that can occur upon utilizing cannabinoids as therapeutic agents.”  https://www.ncbi.nlm.nih.gov/pubmed/30040916

“Glioblastoma (GBM) is the most common and aggressive brain tumor, which causes the highest number of deaths worldwide. It is a highly vascularized tumor, infiltrative, and its tumorigenic capacity is exacerbated. All these hallmarks are therapeutic targets in GBM treatment, including surgical removal followed by radiotherapy and chemotherapy.

Current therapies have not been sufficient for the effective patient’s management, so the classic therapies have had to expand and incorporate new alternative treatments, including natural compounds.

This review summarizes natural products and their physiological effects in in vitro and in vivo models of GBM, specifically by modulating signaling pathways involved in angiogenesis, cell migration/invasion, cell viability, apoptosis, and chemoresistance. The most important aspects of natural products and their derivatives were described in relation to its antitumoral effects.

As a final result, it can be obtained that within the compounds with more evidence that supports or suggests its clinical use are the cannabinoids, terpenes, and curcumin, because many have been shown to have a significant effect in decreasing the progress of GBM through known mechanisms, such as chemo-sensitization or decrease migration and cell invasion.

Natural compounds emerge as promising therapies to attack the progress of GBM.”

  “Glioblastoma multiforme (GBM) is the most frequent and aggressive form of brain cancer. These features are explained at least in part by the high resistance exhibited by these tumors to current anticancer therapies. Thus, the development of novel therapeutic approaches is urgently needed to improve the survival of the patients suffering this devastating disease.

Δ⁹-Tetrahydrocannabinol (THC, the major active ingredient of marijuana), and other cannabinoids have been shown to exert antitumoral actions in animal models of cancer, including glioma. The mechanism of these anticancer actions relies, at least in part, on the ability of these compounds to stimulate autophagy-mediated apoptosis in tumor cells.

Previous observations from our group demonstrated that local administration of THC (or of THC + CBD at a 1:1 ratio, a mixture that resembles the composition of the cannabinoid-based medicine Sativex®) in combination with Temozolomide, the benchmark agent for the treatment of GBM, synergistically reduces the growth of glioma xenografts.

With the aim of optimizing the possible clinical utilization of cannabinoids in anti-GBM therapies, in this work we explored the anticancer efficacy of the systemic administration of cannabinoids in combination with TMZ in preclinical models of glioma.

Our results show that oral administration of THC+CBD (Sativex-like extracts) in combination with TMZ produces a strong antitumoral effect in both subcutaneous and intracranial glioma cell-derived tumor xenografts. In contrast, combined administration of Sativex-like and BCNU (another alkylating agent used for the treatment of GBM which share structural similarities with the TMZ) did not show a stronger effect than individual treatments.

Altogether, our findings support the notion that the combined administration of TMZ and oral cannabinoids could be therapeutically exploited for the management of GBM.”

https://www.ncbi.nlm.nih.gov/pubmed/30125556

https://www.sciencedirect.com/science/article/abs/pii/S0006295218303496

“There is a scarcity of drugs to either prevent or properly manage chemotherapy-induced neuropathic pain (CINP). Cannabis or cannabinoids have been reported to improve pain measures in patients with neuropathic pain.

For this review, a search was done in PubMed for papers that examined the expression of and/or evaluated the use of cannabinoids or drugs that prevent or treat established CINP in a CB receptor-dependent manner in animal models.

Studies suggest there is a specific deficiency of endocannabinoids in the periphery during CINP.

Inhibitors of FAAH and MGL, enzymes that degrade the endocannabinoids, CB receptor agonists, desipramine, and coadministered indomethacin plus minocycline were found to either prevent the development and/or attenuate established CINP in a CB receptor-dependent manner.

The studies analysed suggest that targeting the endocannabinoid system for prevention and treatment of CINP is a plausible therapeutic option. Almost 90% of the studies on animal models of CINP analysed utilised male rodents. Taking into consideration clinical and experimental findings that show gender differences in the mechanisms involved in pain including CINP and in response to analgesics, it is imperative that future studies on CINP utilise more female models.”

“The plant Cannabis sativa L. has been used as an herbal remedy for centuries and is the most important source of phytocannabinoids.

The endocannabinoid system (ECS) consists of receptors, endogenous ligands (endocannabinoids) and metabolizing enzymes, and plays an important role in different physiological and pathological processes.

Phytocannabinoids and synthetic cannabinoids can interact with the components of ECS or other cellular pathways and thus affect the development/progression of diseases, including cancer.

In cancer patients, cannabinoids have primarily been used as a part of palliative care to alleviate pain, relieve nausea and stimulate appetite.

In addition, numerous cell culture and animal studies showed antitumor effects of cannabinoids in various cancer types.

Here we reviewed the literature on anticancer effects of plant-derived and synthetic cannabinoids, to better understand their mechanisms of action and role in cancer treatment. We also reviewed the current legislative updates on the use of cannabinoids for medical and therapeutic purposes, primarily in the EU countries.

In vitro and in vivo cancer models show that cannabinoids can effectively modulate tumor growth, however, the antitumor effects appear to be largely dependent on cancer type and drug dose/concentration.

Understanding how cannabinoids are able to regulate essential cellular processes involved in tumorigenesis, such as progression through the cell cycle, cell proliferation and cell death, as well as the interactions between cannabinoids and the immune system, are crucial for improving existing and developing new therapeutic approaches for cancer patients.

The national legislation of the EU Member States defines the legal boundaries of permissible use of cannabinoids for medical and therapeutic purposes, however, these legislative guidelines may not be aligned with the current scientific knowledge.”

“Previous studies have demonstrated the presence of cannabinoid 2 receptor (CB2R) in the rat cochlea which was induced by cisplatin. In an organ of Corti-derived cell culture model, it was also shown that an agonist of the CB2R protected these cells against cisplatin-induced apoptosis.

In the current study, we determined the distribution of CB2R in the mouse and rat cochleae and examined whether these receptors provide protection against cisplatin-induced hearing loss.

These data unmask a protective role of the cochlear endocannabinoid/CB2R system which appears tonically active under normal conditions to preserve normal hearing. However, an exogenous agonist is needed to boost the activity of endocannabinoid/CB2R system for protection against a more traumatic cochlear insult, as observed with cisplatin administration.”

https://www.ncbi.nlm.nih.gov/pubmed/30186120

https://www.frontiersin.org/articles/10.3389/fncel.2018.00271/full

“Glioblastoma multiforme (GBM) is the most frequent and aggressive type of brain tumor due, at least in part, to its poor response to current anticancer treatments. These features could be explained, at least partially, by the presence within the tumor mass of a small population of cells termed Glioma Initiating Cells (GICs) that has been proposed to be responsible for the relapses occurring in this disease. Thus, the development of novel therapeutic approaches (and specifically those targeting the population of GICs) is urgently needed to improve the survival of the patients suffering this devastating disease.

Previous observations by our group and others have shown that Δ⁹-Tetrahydrocannabinol (THC, the main active ingredient of marijuana) and other cannabinoids including cannabidiol (CBD) exert antitumoral actions in several animal models of cancer, including gliomas.

We also found that the administration of THC (or of THC + CBD at a 1:1 ratio) in combination with temozolomide, the benchmark agent for the treatment of GBM, synergistically reduces the growth of glioma xenografts.

In this work we investigated the effect of the combination of TMZ and THC:CBD mixtures containing different ratios of the two cannabinoids in preclinical glioma models, including those derived from GICs.

Our findings show that TMZ + THC:CBD combinations containing a higher proportion of CDB (but not TMZ + CBD alone) produce a similar antitumoral effect as the administration of TMZ together with THC and CBD at a 1:1 ratio in xenografts generated with glioma cell lines. In addition, we also found that the administration of TMZ + THC:CBD at a 1:1 ratio reduced the growth of orthotopic xenografts generated with GICs derived from GBM patients and enhanced the survival of the animals bearing these intracranial xenografts.

Remarkably, the antitumoral effect observed in GICs-derived xenografts was stronger when TMZ was administered together with cannabinoid combinations containing a higher proportion of CBD. These findings support the notion that the administration of TMZ together with THC:CBD combinations – and specifically those containing a higher proportion of CBD – may be therapeutically explored to target the population of GICs in GBM.”

“As cancer therapies improve, patients are living longer. With these improvements in therapy comes a responsibility to optimize patients’ quality of life during cancer therapy and beyond. This report reviews three timely and important topics.

The first section reviews the mechanism underlying chemotherapy-induced peripheral neuropathy and evaluates the evidence for interventions to prevent and treat peripheral neuropathy. It also provides a framework for approaching the diagnosis and management of this common and bothersome side effect.

The second section addresses the controversial but effective use of cannabinoids for cancer and chemotherapy symptoms. Although clinical trials are difficult to conduct because of the political and social stigma of this class of drugs, this review provides evidence of the efficacy of cannabinoids for treatment of pain and nausea.

The last section addresses the mind-body connection, with a focus on the negative emotions patients with cancer often experience. This section assesses the literature regarding mindfulness-based programs to improve cancer-related stress. These three topics may appear unrelated, but all address one common goal: treating the body and the mind to optimize quality of life during and after cancer therapy.”

“Triple negative breast cancer (TNBC) is the deadliest form of breast cancer because compared with other types of breast cancer, it is more aggressive, diagnosed at later stage and more likely to develop recurrence.

Many patients do not experience adequate tumor control after current clinical treatments involving surgical removal, chemotherapy and/or radiotherapy, leading to disease progression and significantly decreased quality of life.

Here we report a new combinatory therapy strategy involving cannabinoid-based medicine and photodynamic therapy (PDT) for the treatment of TNBC.

This combinatory therapy targets two proteins upregulated in TNBC: the cannabinoid CB2 receptor (CB₂R, a G-protein coupled receptor) and translocator protein (TSPO, a mitochondria membrane receptor). We found that the combined CB₂R agonist and TSPO-PDT treatment resulted in synergistic inhibition in TNBC cell and tumor growth.

This combinatory therapy approach provides new opportunities to treat TNBC with high efficacy. In addition, this study provides new evidence on the therapeutic potential of CB₂R agonists for cancer.”

https://www.ncbi.nlm.nih.gov/pubmed/30240926

https://www.sciencedirect.com/science/article/pii/S1572100018301571?via%3Dihub