Possible Enhancement of Photodynamic Therapy (PDT) Colorectal Cancer Treatment when Combined with Cannabidiol.

“Colorectal cancer (CRC) has a high mortality rate and is one of the most difficult diseases to manage due to tumour resistance and metastasis. The treatment of choice for CRC is reliant on the phase and time of diagnosis. Despite several conventional treatments available to treat CRC (surgical excision, chemo-, radiation- and immune-therapy), resistance is a major challenge, especially if it has metastasized. Additionally, these treatments often cause unwanted adverse side effects and so it remains imperative to investigate, alternative combination therapies.

Photodynamic Therapy (PDT) is a promising treatment modality for the primary treatment of CRC, since it is non-invasive, has few side effects and selectively damages only cancerous tissues, leaving adjacent healthy structures intact. PDT involves three fundamentals: a Photosensitizer (PS) drug localized in tumour tissues, oxygen and light. Upon PS excitation using a specific wavelength of light, an energy transfer cascade occurs, that ultimately yields cytotoxic species, which in turn induces cell death.

Cannabidiol (CBD) is a cannabinoid compound derived from the Cannabis sativa plant, which is found to exert anticancer effects on CRC through different pathways, inducing apoptosis and so inhibits tumour metastasis and secondary spread.

This review paper highlights current conventional treatment modalities for CRC and their limitations, as well as discusses the necessitation for further investigation into unconventional active nanoparticle targeting PDT treatments for enhanced primary CRC treatment. This can be administered in combination with CBD, to prevent CRC secondary spread and so enhance the synergistic efficacy of CRC treatment outcomes, with less side effects.”

https://www.ncbi.nlm.nih.gov/pubmed/32294046

http://www.eurekaselect.com/180902/article

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Cannabinoids as anticancer therapeutic agents.

Cell Cycle Journal are Co-Sponsoring #ACCM15 – The Cell Division Lab “The recent announcement of marijuana legalization in Canada spiked many discussions about potential health benefits of Cannabis sativaCannabinoids are active chemical compounds produced by cannabis, and their numerous effects on the human body are primarily exerted through interactions with cannabinoid receptor types 1 (CB1) and 2 (CB2). Cannabinoids are broadly classified as endo-, phyto-, and synthetic cannabinoids. In this review, we will describe the activity of cannabinoids on the cellular level, comprehensively summarize the activity of all groups of cannabinoids on various cancers and propose several potential mechanisms of action of cannabinoids on cancer cells.”

https://www.ncbi.nlm.nih.gov/pubmed/32249682

“Endocannabinoids and phytocannabinoids can be used for cancer therapy. Cannabis extracts have stronger anti-tumor capacity than single cannabinoids. Combination of several cannabinoids may have more potent effect on cancer.”

https://www.tandfonline.com/doi/abs/10.1080/15384101.2020.1742952?journalCode=kccy20

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The Endocannabinoid System: A Target for Cancer Treatment.

ijms-logo“In recent years, the endocannabinoid system has received great interest as a potential therapeutic target in numerous pathological conditions.

Cannabinoids have shown an anticancer potential by modulating several pathways involved in cell growth, differentiation, migration, and angiogenesis.

However, the therapeutic efficacy of cannabinoids is limited to the treatment of chemotherapy-induced symptoms or cancer pain, but their use as anticancer drugs in chemotherapeutic protocols requires further investigation.

In this paper, we reviewed the role of cannabinoids in the modulation of signaling mechanisms implicated in tumor progression.”

https://www.ncbi.nlm.nih.gov/pubmed/31979368

https://www.mdpi.com/1422-0067/21/3/747

“In addition to the symptomatic therapy of cancer patients, the antitumor effects of cannabinoids (whether in monotherapy or in combination with other cancer therapies) have promising potential in the treatment of cancer patients.”   https://www.ncbi.nlm.nih.gov/pubmed/31950844
“In addition to the well-known palliative effects of cannabinoids on some cancer-associated symptoms, a large body of evidence shows that these molecules can decrease tumour growth in animal models of cancer. In addition, cannabinoids inhibit angiogenesis and decrease metastasis in various tumour types in laboratory animals. Thus, numerous studies have provided evidence that thc and other cannabinoids exhibit antitumour effects in a wide array of animal models of cancer.”  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4791144/


“Antitumour actions of cannabinoids.”   https://www.ncbi.nlm.nih.gov/pubmed/30019449 

“The endocannabinoid system as a target for the development of new drugs for cancer therapy” https://www.ncbi.nlm.nih.gov/pubmed/12723496

“Cannabinoids as Anticancer Drugs.”  https://www.ncbi.nlm.nih.gov/pubmed/28826542

http://www.thctotalhealthcare.com/category/cancer/

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Effects of O-1602 and CBD on TNBS-induced colonic disturbances.

Neurogastroenterology & Motility banner“This study attempted to provide the effects and mechanisms of two cannabinoids, O-1602 and cannabidiol (CBD), on colonic motility of 2,4,6-trinitro-benzene sulfonic acid (TNBS) colitis.

METHODS:

TNBS was used to induce the model of motility disorder. G protein-coupled receptor 55 (GPR55) expression was detected using real-time PCR and immunohistochemistry in colon. Pro-inflammatory cytokines and myeloperoxidase were also measured. The colonic motility was measured by upper GI transit in vivo and recorded using electrical stimulation organ bath technique in vitro. Freshly isolated smooth muscle from the rat colon were applied to determine the membrane potential and Ca2+ -ATPase activity, respectively.

KEY RESULTS:

CBD or O-1602 separately improved inflammatory conditions significantly in TNBS-induced colitis rats. However, sole CBD pretreatment reduced GPR55 expression, which was up-regulated in TNBS colitis. O-1602 and CBD each lowered MPO and IL-6 levels remarkably in TNBS colitis, while TNF-α levels experienced no change. CBD rescued the downward colonic motility in TNBS colitis in vivo; however, it decreased the upward contraction of the smooth muscle strip under electrical stimulation in vitro. Pretreatment with CBD prevented against TNBS-induced changes of Ca2+ -ATPase activity of smooth muscle cells. However, membrane potential of the smooth muscle cells decreased by TNBS experienced no change after O-1602 or CBD import.

CONCLUSIONS & INFERENCES:

The present study suggested that CBD participated in the regulation of colonic motility in rats, and the mechanisms may be involved in the regulation of inlammatory factors and Ca2+ -ATPase activity through GPR55.”

https://www.ncbi.nlm.nih.gov/pubmed/31802588

https://onlinelibrary.wiley.com/doi/abs/10.1111/nmo.13756

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Antiproliferative and antioxidant effect of polar hemp extracts (Cannabis sativa L., Fedora cv.) in human colorectal cell lines.

Publication Cover “Total phenolic content and antioxidant activity of polar extracts of edible resources from Fedora hemp cultivar (Cannabis sativa L.), namely seed, flour and oil, were evaluated. The main components in the polar extracts were identified using HPLC-DAD and HPLC-ESI-MS/MS. As expected, the molecular profile of components from seeds and flour was strictly similar, dominated by N-trans-caffeoyltyramine. The profile of oil polar extracts contained hydroxycinnamic acid derivatives and cannabinoids at lower extent. While the extracts from hemp seed and flour did not interfere with growth of Caco-2 and HT-29 cell, the one from oil (150 µg/mL) significantly reduced cell viability after 24 h of treatment. This effect was associated with the activation of apoptotic cell death and was independent from the antioxidant capacity of the oil polar extract. Notably, HT-29 cells differentiated with sodium butyrate were not sensitive to the cytotoxic effect of the oil extract.”

https://www.ncbi.nlm.nih.gov/pubmed/31544542

https://www.tandfonline.com/doi/abs/10.1080/09637486.2019.1666804?journalCode=iijf20

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Preclinical evidence on the anticancer properties of phytocannabinoids

Image result for CROSBI“Phytocannabinoids are unique terpenophenolic compounds predominantly produced in the glandular trichomes of the cannabis plant (Cannabis sativa L.). The delta-9- tetrahydrocannabinol (THC) is the main active constituent responsible for the plant’s psychoactive effect and, together with the non- psychoactive cannabidiol (CBD), the most investigated naturally occurring cannabinoid.

The first report on the antitumor properties of cannabis compounds appeared more than forty years ago, but the potential of targeting the endocannabinoid system in cancer has recently attracted increasing interest. Our study aimed to review the last decade’s findings on the anticancer potential of plant- derived cannabinoids and the possible mechanisms of their activity.

A large body of in vitro data has been accumulated demonstrating that phytocannabinoids affect a wide spectrum of tumor cells, including gliomas, neuroblastomas, hepatocarcinoma as well as skin, prostate, breast, cervical, colon, pancreatic, lung and hematological cancer.

It has been found that they can stop the uncontrolled growth of cancer cells through the cell-cycle arrest, inhibition of cell proliferation and induction of autophagy and apoptosis. They can also block all the steps of tumor progression, including tumor cell migration, adhesion and invasion as well as angiogenesis. The observed effects are mainly mediated by the cannabinoid CB1 and/or CB2 receptors, although some other receptors and mechanisms unrelated to receptor stimulation may also be involved.

The majority of available animal studies confirmed that phytocannabinoids are capable of effectively decreasing cancer growth and metastasis in vivo. THC was found to be effective against experimental glioma, liver, pancreatic, breast and lung cancer while CBD showed activity against glioma and neuroblastoma, melanoma, colon, breast, prostate and lung cancer. Further in vitro and in vivo studies also greatly support their use in combination with traditional chemotherapy or radiotherapy, which results in improved efficiency, attenuated toxicity or reduced drug resistance.

Taken together most of available preclinical results emphasize the extensive therapeutic potential of THC and CBD in various types of cancers. The potential clinical interest of cannabinoids is additionally suggested by their selectivity for tumor cells as well as their good tolerance and the absence of normal tissue toxicity, which are still the major limitations of most conventional drugs. The accumulated preclinical evidence strongly suggests the need for clinical testing of cannabinoids in cancer patients.”

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The heterogeneity and complexity of Cannabis extracts as antitumor agents

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“The Cannabis plant contains over 100 phytocannabinoids and hundreds of other components. The biological effects and interplay of these Cannabis compounds are not fully understood and yet influence the plant’s therapeutic effects.

Here we assessed the antitumor effects of whole Cannabis extracts, which contained significant amounts of differing phytocannabinoids, on different cancer lines from various tumor origins.

Our results show that specific Cannabis extracts impaired the survival and proliferation of cancer cell lines as well as induced apoptosis.

Our findings showed that pure (-)-Δ9trans-tetrahydrocannabinol (Δ9-THC) did not produce the same effects on these cell lines as the whole Cannabis extracts. Furthermore, Cannabis extracts with similar amounts of Δ9-THC produced significantly different effects on the survival of specific cancer cells.

In addition, we demonstrated that specific Cannabis extracts may selectively and differentially affect cancer cells and differing cancer cell lines from the same organ origin. We also found that cannabimimetic receptors were differentially expressed among various cancer cell lines and suggest that this receptor diversity may contribute to the heterogeneous effects produced by the differing Cannabis extracts on each cell line.

Our overall findings indicate that the effect of a Cannabis extract on a specific cancer cell line relies on the extract’s composition as well as on certain characteristics of the targeted cells.”

http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=26983

“Many previous reports highlight and demonstrate the anti-tumor effects of cannabinoids. In the last decade, accumulating evidence has indicated that phytocannabinoids might have antitumor properties. A number of in vitro and in vivo studies have demonstrated the effects of phytocannabinoids on tumor progression by interrupting several characteristic features of cancer. These studies suggest that specific cannabinoids such as Δ9-THC and CBD induce apoptosis and inhibit proliferation in various cancer cell lines.”

http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path%5B%5D=26983&path%5B%5D=85698

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Antitumor Cannabinoid Chemotypes: Structural Insights.

Image result for frontiers in pharmacology“Cannabis has long been known to limit or prevent nausea and vomiting, lack of appetite, and pain. For this reason, cannabinoids have been successfully used in the treatment of some of the unwanted side effects caused by cancer chemotherapy.

Besides their palliative effects, research from the past two decades has demonstrated their promising potential as antitumor agents in a wide variety of tumors.

Cannabinoids of endogenous, phytogenic, and synthetic nature have been shown to impact the proliferation of cancer through the modulation of different proteins involved in the endocannabinoid system such as the G protein-coupled receptors CB1, CB2, and GRP55, the ionotropic receptor TRPV1, or the fatty acid amide hydrolase (FAAH).

In this article, we aim to structurally classify the antitumor cannabinoid chemotypes described so far according to their targets and types of cancer. In a drug discovery approach, their in silico pharmacokinetic profile has been evaluated in order to identify appropriate drug-like profiles, which should be taken into account for further progress toward the clinic.

This analysis may provide structural insights into the selection of specific cannabinoid scaffolds for the development of antitumor drugs for the treatment of particular types of cancer.” https://www.ncbi.nlm.nih.gov/pubmed/31214034

“The first report on the antitumor activity of phytocannabinoids was published over four decades ago. During these last years, significant research has been focused on the therapeutic potential of cannabinoids to manage palliative effects in cancer patients. Besides such palliative applications, some cannabinoids have shown anticancer properties. Since inflammation is a common risk factor for cancer, and some cannabinoids have shown anti-inflammatory properties, they could play a role in chemoprevention.” https://www.frontiersin.org/articles/10.3389/fphar.2019.00621/full
“Antitumor effects of THC.” http://www.ncbi.nlm.nih.gov/pubmed/11097557
“Antitumor effects of cannabidiol” http://www.ncbi.nlm.nih.gov/pubmed/14617682
“Anti-tumour actions of cannabinoids.” https://www.ncbi.nlm.nih.gov/pubmed/30019449
“Extensive preclinical research has demonstrated that cannabinoids, the active ingredients of Cannabis sativa, trigger antitumor responses in different models of cancer.” https://www.ncbi.nlm.nih.gov/pubmed/29940172
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Cannabidiol Overcomes Oxaliplatin Resistance by Enhancing NOS3- and SOD2-Induced Autophagy in Human Colorectal Cancer Cells.

cancers-logo

“Although oxaliplatin is an effective chemotherapeutic drug for colorectal cancer (CRC) treatment, patients often develop resistance to it. Therefore, a new strategy for CRC treatment is needed.

The purpose of this study was to determine the effect of cannabidiol(CBD), one of the components of the cannabis plant, in overcoming oxaliplatin resistance in CRC cells.

Taken together, these results suggest that elevated phosphorylation of NOS3 is essential for oxaliplatin resistance. The combination of oxaliplatin and CBD decreased NOS3 phosphorylation, which resulted in autophagy, by inducing the overproduction of ROS through mitochondrial dysfunction, thus overcoming oxaliplatin resistance.”

https://www.ncbi.nlm.nih.gov/pubmed/31195721

https://www.mdpi.com/2072-6694/11/6/781

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Should Oncologists Recommend Cannabis?

“Cannabis is a useful botanical with a wide range of therapeutic potential. Global prohibition over the past century has impeded the ability to study the plant as medicine. However, delta-9-tetrahydrocannabinol (THC) has been developed as a stand-alone pharmaceutical initially approved for the treatment of chemotherapy-related nausea and vomiting in 1986. The indication was expanded in 1992 to include treatment of anorexia in patients with the AIDS wasting syndrome. Hence, if the dominant cannabinoid is available as a schedule III prescription medication, it would seem logical that the parent botanical would likely have similar therapeutic benefits. The system of cannabinoid receptors and endogenous cannabinoids (endocannabinoids) has likely developed to help us modulate our response to noxious stimuli. Phytocannabinoids also complex with these receptors, and the analgesic effects of cannabis are perhaps the best supported by clinical evidence. Cannabis and its constituents have also been reported to be useful in assisting with sleep, mood, and anxiety. Despite significant in vitro and animal model evidence supporting the anti-cancer activity of individual cannabinoids-particularly THC and cannabidiol (CBD)-clinical evidence is absent. A single intervention that can assist with nausea, appetite, pain, mood, and sleep is certainly a valuable addition to the palliative care armamentarium. Although many healthcare providers advise against the inhalation of a botanical as a twenty-first century drug-delivery system, evidence for serious harmful effects of cannabis inhalation is scant and a variety of other methods of ingestion are currently available from dispensaries in locales where patients have access to medicinal cannabis. Oncologists and palliative care providers should recommend this botanical remedy to their patients to gain first-hand evidence of its therapeutic potential despite the paucity of results from randomized placebo-controlled clinical trials to appreciate that it is both safe and effective and really does not require a package insert.”

https://www.ncbi.nlm.nih.gov/pubmed/31161270

https://link.springer.com/article/10.1007%2Fs11864-019-0659-9

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