Category Archives: Bone cancer

The Effect of Cannabinoids on Single-level Lumbar Arthrodesis Outcomes in a Rat Model

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“Background context: The opioid epidemic is a public health crisis affecting spine care and pain management. Medical marijuana is a potential non-opioid analgesic yet to be studied in the surgical setting since its effects on bone healing are not fully understood. Studies have demonstrated analgesic and potentially osteoinductive properties of cannabinoids with endocannabinoid receptor expression in bone tissue.

Purpose: We hypothesize that tetrahydrocannabinol (THC) and cannabidiol (CBD) will not decrease bone healing in spinal fusion.

Study design: Seventy-eight adult Sprague-Dawley rats were used for this study. Utilizing allogenic bone grafts (6 donor rats), posterolateral inter-transverse lumbar fusion at the L4-L5 level was performed. The animals were equally divided into four treatment groups, each receiving 0.1ml intraperitoneal injections weekly as follows: placebo (saline), 5mg/kg THC, 5mg/kg CBD, and a combination of 5mg/kg THC and 5mg/kg CBD (Combo).

Methods: Callus tissue was harvested 2- and 8-weeks post-surgery for qPCR assessment to quantify changes in the expression of osteogenic genes. Manual palpation was done to assess the strength of the L4-L5 arthrodesis on all rats. μCT image-based callus analysis and histology were performed. One-way ANOVA followed by post hoc comparisons was performed.

Results: μCT demonstrated no significant differences. Treatment groups had slightly increased bone volume and density compared to control. qPCR at two weeks indicated downregulated RANKL/OPG ratios skewing towards osteogenesis in the CBD group, with the THC and CBD+THC groups demonstrating a downward trend (P>0.05). ALPL, BMP4, and SOST were significantly higher in the CBD group, with CTNNB1 and RUNX2 also showing an upregulating trend. The CBD group showed elevation in Col1A1 and MMP13. Data at eight weeks showed ALPL, RUNX2, BMP4, and SOST were downregulated for all treatment groups. In the CBD+THC group, RANK, RANKL, and OPG were downregulated. OPG downregulation reached significance for the THC and CBD+THC group compared to saline. Interestingly, the RANKL/OPG ratio showed upregulation in the CBD and CBD+THC groups. RANKL showed upregulation in the CBD group. At 2 and 8 weeks, the CBD treatment group showed superior histological progression, increasing between time points.

Conclusion: This study demonstrates that CBD and THC have no adverse effect on bone healing and the rate of spinal fusion in rats. Osteogenic factors were upregulated in the CBD-treated groups at two weeks, which indicates a potential for bone regeneration. In this group, compared to control, the RANKL/OPG ratio at the early healing phase demonstrates the inhibition of osteoclast differentiation, enhancing bone formation. Interestingly, it shows promoted osteoclast differentiation at the later healing phase, enhancing bone remodeling. This aligns with the physiological expectation of a lower ratio in the early phases and a higher ratio in the later remodeling phases.

Clinical significance: CBD and THC showed no inhibitory effects on bone healing in a spinal fusion model. Moreover, histologic and gene expression analysis demonstrated that CBD may, in fact, enhance bone healing. Further research is needed to confirm the safe usage of THC and CBD in the post-operative setting following spinal fusions.”

https://pubmed.ncbi.nlm.nih.gov/38704096/

https://www.thespinejournalonline.com/article/S1529-9430(24)00217-1/abstract

Therapeutic targeting of the tumor microenvironments with cannabinoids and their analogs: Update on clinical trials

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“Cancer is a major global public health concern that affects both industrialized and developing nations. Current cancer chemotherapeutic options are limited by side effects, but plant-derived alternatives and their derivatives offer the possibilities of enhanced treatment response and reduced side effects.

A plethora of recently published articles have focused on treatments based on cannabinoids and cannabinoid analogs and reported that they positively affect healthy cell growth and reverse cancer-related abnormalities by targeting aberrant tumor microenvironments (TMEs), lowering tumorigenesis, preventing metastasis, and/or boosting the effectiveness of chemotherapy and radiotherapy.

Furthermore, TME modulating systems are receiving much interest in the cancer immunotherapy field because it has been shown that TMEs have significant impacts on tumor progression, angiogenesis, invasion, migration, epithelial to mesenchymal transition, metastasis and development of drug resistance.

Here, we have reviewed the effective role of cannabinoids, their analogs and cannabinoid nano formulations on the cellular components of TME (endothelial cells, pericytes, fibroblast and immune cells) and how efficiently it retards the progression of carcinogenesis is discussed. The article summarizes the existing research on the molecular mechanisms of cannabinoids regulation of the TME and finally highlights the human studies on cannabinoids’ active interventional clinical trials.

The conclusion outlines the need for future research involving clinical trials of cannabinoids to demonstrate their efficacy and activity as a treatment/prevention for various types of human malignancies.”

https://pubmed.ncbi.nlm.nih.gov/37146933/

https://www.sciencedirect.com/science/article/abs/pii/S0013935123006540?via%3Dihub

The Effectiveness and Safety of Medical Cannabis for Treating Cancer Related Symptoms in Oncology Patients

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Frontiers in Pain Research (@FrontPain) / Twitter

“The use of medical cannabis (MC) to treat cancer-related symptoms is rising. However, there is a lack of long-term trials to assess the benefits and safety of MC treatment in this population. In this work, we followed up prospectively and longitudinally on the effectiveness and safety of MC treatment.

Oncology patients reported on multiple symptoms before and after MC treatment initiation at one-, three-, and 6-month follow-ups. Oncologists reported on the patients’ disease characteristics. Intention-to-treat models were used to assess changes in outcomes from baseline. MC treatment was initiated by 324 patients and 212, 158 and 126 reported at follow-ups.

Most outcome measures improved significantly during MC treatment for most patients (p < 0.005). Specifically, at 6 months, total cancer symptoms burden declined from baseline by a median of 18%, from 122 (82–157) at baseline to 89 (45–138) at endpoint (−18.98; 95%CI= −26.95 to −11.00; p < 0.001). Reported adverse effects were common but mostly non-serious and remained stable during MC treatment.

The results of this study suggest that MC treatment is generally safe for oncology patients and can potentially reduce the burden of associated symptoms with no serious MC-related adverse effects.

The main finding of the current study is that most cancer comorbid symptoms improved significantly during 6 months of MC treatment.

Additionally, we found that MC treatment in cancer patients was well tolerated and safe.”

https://pubmed.ncbi.nlm.nih.gov/35669038/

https://www.frontiersin.org/articles/10.3389/fpain.2022.861037/full?utm_source=fweb

“Cancer Pain Treatment Using Marijuana Safe and Effective, Large Study Finds”

https://www.newsweek.com/cannabis-medicinal-cancer-patient-symptoms-pain-relief-1711981


Synthesis of A Tetrahydrocannabinol (THC) Analog For Analyzing Cellular Proliferation in Concert With Epigallocatechin Gallate (EGCG) on A Bone-like Cancer Cell Line (UMR 106-01 BSP)

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“Cannabinoids have been extensively studied in the field of cancer research. Tetrahydrocannabinol (THC) has shown promising results in influencing cellular proliferation when in association with other cannabinoids. This traditional entourage effect solely focuses on the study of THC with other cannabinoids. However, not many studies have been done to explore the synergistic effect of THC analogs when used with non-cannabinoid compounds. THC in its isolate form for experimentation is very strictly regulated. Therefore, this study was conducted in the pursuit of synthesizing and experimenting with analogs of THC to observe a potential entourage effect with epigallocatechin gallate (EGCG), a compound known for its efficacy to reduce proliferation at higher concentrations in UMR cells. It was hypothesized that active analogs of THC can be synthesized and used in concert with EGCG to potentiate decreased proliferation in the bone-like cancer cell line UMR 106-01 BSP (UMR cells). Briefly, a Knoevenagel condensation and a Diels-Alder reaction using 1,3-cyclohexanediol dissolved in methanol (MeOH) and citronellal with ethylenediamine diacetic acid (EDDA) at a temperature of 60℃ was used to synthesize a novel THC analog, 3,10,10-Trimethyl-1,2,3,4,4a,6,7,8,10,10a-decahydro-9-oxa-5-phenanthrenone (TDP). UMR cells were routinely passaged, counted, plated in six-well culture plates at 480,00 cells/mL, then treated with 10-fold dilutions of TDP. The plates were incubated for 72 hours in a humidified incubator at 37 degrees Celsius with 5% carbon dioxide infusion. At the end of the experiment, the cells were routinely washed with HANKS buffered saline solution (HBSS), then routinely counted using the Luna Automated Cell Counter. In another experiment, designated cells were co-treated with TDP+EGCG, following the protocol above. F test ANOVA was used to compare variances and all values in the results were expressed as means ± SD. The results from the attempted cannabinoid analog synthesis yielded a novel active THC analog, TDP. Serial dilutions treatment of the UMR cells with TDP alone showed its ability to decrease cell count in a concentration dependent manner. However, when coupled with higher concentrations of EGCG, the co-treatment increased cell count rather than potentiating the effect of decreasing cellular proliferation. The F Test ANOVA showed robust statistical significance (p values <0.05) with regard to TDP’s effect of decreasing cell proliferation in UMR cells in a concentration-dependent manner. Overall, the outcomes of this study suggest that active forms of THC analogs can be synthesized and tested in concert with other non-cannabinoid compounds like EGCG. This study opens the door to explore the entourage effect of TDP with other non-cannabinoid compounds that may provide another tool in the therapeutic treatment of bone cancer cells.”

https://pubmed.ncbi.nlm.nih.gov/35555816/

https://faseb.onlinelibrary.wiley.com/doi/10.1096/fasebj.2022.36.S1.L8061

The Endocannabinoid System as a Pharmacological Target for New Cancer Therapies

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“Despite the long history of cannabinoid use for medicinal and ritual purposes, an endogenous system of cannabinoid-controlled receptors, as well as their ligands and the enzymes that synthesise and degrade them, was only discovered in the 1990s. Since then, the endocannabinoid system has attracted widespread scientific interest regarding new pharmacological targets in cancer treatment among other reasons.

Meanwhile, extensive preclinical studies have shown that cannabinoids have an inhibitory effect on tumour cell proliferation, tumour invasion, metastasis, angiogenesis, chemoresistance and epithelial-mesenchymal transition (EMT) and induce tumour cell apoptosis and autophagy as well as immune response. Appropriate cannabinoid compounds could moreover be useful for cancer patients as potential combination partners with other chemotherapeutic agents to increase their efficacy while reducing unwanted side effects.

In addition to the direct activation of cannabinoid receptors through the exogenous application of corresponding agonists, another strategy is to activate these receptors by increasing the endocannabinoid levels at the corresponding pathological hotspots. Indeed, a number of studies accordingly showed an inhibitory effect of blockers of the endocannabinoid-degrading enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) on tumour development and spread.

This review summarises the relevant preclinical studies with FAAH and MAGL inhibitors compared to studies with cannabinoids and provides an overview of the regulation of the endocannabinoid system in cancer.”

https://pubmed.ncbi.nlm.nih.gov/34830856/

“Cannabinoids have been shown to suppress tumour cell proliferation, tumour invasion, metastasis, angiogenesis, chemoresistance and epithelial-mesenchymal transition and to induce tumour cell apoptosis, autophagy and immune response. This review focuses on the current status of investigations on the impact of inhibitors of endocannabinoid-degrading enzymes on tumour growth and spread in preclinical oncology research.”

https://www.mdpi.com/2072-6694/13/22/5701


Plant-derived cannabinoids as anticancer agents

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“Substantial preclinical evidence demonstrates the antiproliferative, cytotoxic, and antimetastatic properties of plant-derived cannabinoids (phytocannabinoids) such as cannabidiol and tetrahydrocannabinol. The cumulative body of research into the intracellular mechanisms and phenotypic effects of these compounds supports a logical, judicious progression to large-scale phase II/III clinical trials in certain cancer types to truly assess the efficacy of phytocannabinoids as anticancer agents.”

https://pubmed.ncbi.nlm.nih.gov/35260379/

Cannabinoids as anticancer drugs: current status of preclinical research

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“Drugs that target the endocannabinoid system are of interest as pharmacological options to combat cancer and to improve the life quality of cancer patients. From this perspective, cannabinoid compounds have been successfully tested as a systemic therapeutic option in a number of preclinical models over the past decades. As a result of these efforts, a large body of data suggests that the anticancer effects of cannabinoids are exerted at multiple levels of tumour progression via different signal transduction mechanisms. Accordingly, there is considerable evidence for cannabinoid-mediated inhibition of tumour cell proliferation, tumour invasion and metastasis, angiogenesis and chemoresistance, as well as induction of apoptosis and autophagy. Further studies showed that cannabinoids could be potential combination partners for established chemotherapeutic agents or other therapeutic interventions in cancer treatment. Research in recent years has yielded several compounds that exert promising effects on tumour cells and tissues in addition to the psychoactive Δ9-tetrahydrocannabinol, such as the non-psychoactive phytocannabinoid cannabidiol and inhibitors of endocannabinoid degradation. This review provides an up-to-date overview of the potential of cannabinoids as inhibitors of tumour growth and spread as demonstrated in preclinical studies.”

https://pubmed.ncbi.nlm.nih.gov/35277658/

Cannabidiol and Other Phytocannabinoids as Cancer Therapeutics

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“Preclinical models provided ample evidence that cannabinoids are cytotoxic against cancer cells. Among the best studied phytocannabinoids, cannabidiol (CBD) is most promising for the treatment of cancer as it lacks the psychotomimetic properties of delta-9-tetrahydrocannabinol (THC). In vitro studies and animal experiments point to a concentration- (dose-)dependent anticancer effect. The effectiveness of pure compounds versus extracts is the subject of an ongoing debate. Actual results demonstrate that CBD-rich hemp extracts must be distinguished from THC-rich cannabis preparations. Whereas pure CBD was superior to CBD-rich extracts in most in vitro experiments, the opposite was observed for pure THC and THC-rich extracts, although exceptions were noted. The cytotoxic effects of CBD, THC and extracts seem to depend not only on the nature of cannabinoids and the presence of other phytochemicals but also largely on the nature of cell lines and test conditions. Neither CBD nor THC are universally efficacious in reducing cancer cell viability. The combination of pure cannabinoids may have advantages over single agents, although the optimal ratio seems to depend on the nature of cancer cells; the existence of a ‘one size fits all’ ratio is very unlikely. As cannabinoids interfere with the endocannabinoid system (ECS), a better understanding of the circadian rhythmicity of the ECS, particularly endocannabinoids and receptors, as well as of the rhythmicity of biological processes related to the growth of cancer cells, could enhance the efficacy of a therapy with cannabinoids by optimization of the timing of the administration, as has already been reported for some of the canonical chemotherapeutics. Theoretically, a CBD dose administered at noon could increase the peak of anandamide and therefore the effects triggered by this agent. Despite the abundance of preclinical articles published over the last 2 decades, well-designed controlled clinical trials on CBD in cancer are still missing. The number of observations in cancer patients, paired with the anticancer activity repeatedly reported in preclinical in vitro and in vivo studies warrants serious scientific exploration moving forward.”

https://pubmed.ncbi.nlm.nih.gov/35244889/

Cannabis as a potential compound against various malignancies, legal aspects, advancement by exploiting nanotechnology and clinical trials

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“Various preclinical and clinical studies exhibited the potential of cannabis against various diseases, including cancer and related pain. Subsequently, many efforts have been made to establish and develop cannabis-related products and make them available as prescription products. Moreover, FDA has already approved some cannabis-related products, and more advancement in this aspect is still going on. However, the approved product of cannabis is in oral dosage form, which exerts various limitations to achieve maximum therapeutic effects. A considerable translation is on a hike to improve bioavailability, and ultimately, the therapeutic efficacy of cannabis by the employment of nanotechnology. Besides the well-known psychotropic effects of cannabis upon the use at high doses, literature has also shown the importance of cannabis and its constituents in minimising the lethality of cancer in the preclinical models. This review discusses the history of cannabis, its legal aspect, safety profile, the mechanism by which cannabis combats with cancer, and the advancement of clinical therapy by exploiting nanotechnology. A brief discussion related to the role of cannabinoid in various cancers has also been incorporated. Lastly, the information regarding completed and ongoing trials have also been elaborated.”

https://pubmed.ncbi.nlm.nih.gov/35321629/

Cannabidiol promotes apoptosis of osteosarcoma cells in vitro and in vivo by activating the SP1-CBX2 axis

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“Osteosarcoma is the most common primary malignant bone tumor that often occurs in children, adolescents, and young adults. Cannabidiol plays an essential role in cancer treatment. However, its effects on osteosarcoma have not yet been addressed. In the present study, we investigated the pharmacological effects of cannabidiol on osteosarcoma. We found that cannabidiol effectively suppressed the proliferation and colony formation of osteosarcoma cells. Further studies showed that cannabidiol significantly promoted cell apoptosis and changes in cell apoptosis-related gene proteins in vitro. In addition, cannabidiol administration inhibited tumor growth and promoted the apoptosis of osteosarcoma cells in a mouse xenograft model. The in vitro study also demonstrated that SP1 contributes to chromobox protein homolog 2 (CBX2) reduction in cannabidiol-treated MG63 and HOS cells, and that cannabidiol may recruit SP1 into the CBX2 promoter regions to downregulate CBX2 expression at the transcriptional level and promote osteosarcoma cell apoptosis. Further, the result showed that cannabidiol suppressed osteosarcoma cell migration. In summary, cannabidiol effectively promoted the apoptosis of osteosarcoma cells in vitro and in vivo and suppressed tumor growth in a mouse xenograft model by regulating the SP1-CBX2 axis. This finding provides novel therapeutic strategies for osteosarcoma in the clinic.”

https://pubmed.ncbi.nlm.nih.gov/35273722/