Category Archives: Bladder Cancer

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

Anticancer properties of cannabidiol and Δ9-tetrahydrocannabinol and synergistic effects with gemcitabine and cisplatin in bladder cancer cell lines

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ISRCTN - Publish with BMC

“Introduction: With the legalization of cannabis in multiple jurisdictions throughout the world, a larger proportion of the population consumes cannabis. Several studies have demonstrated anti-tumor effects of components present in cannabis in different models. Unfortunately, little is known about the potential anti-tumoral effects of cannabinoids in bladder cancer and how cannabinoids could potentially synergize with chemotherapeutic agents. Our study aims to identify whether a combination of cannabinoids, like cannabidiol and Δ9-tetrahydrocannabinol, with agents commonly used to treat bladder cancer, such as gemcitabine and cisplatin, can produce desirable synergistic effects. We also evaluated if co-treatment with different cannabinoids resulted in synergistic effects.

Methods: We generated concentration curves with several drugs, including several cannabinoids, to identify the range at which they could exert anti-tumor effects in bladder cancer cell lines. We tested the cytotoxic effects of gemcitabine (up to 100 nM), cisplatin (up to 100 μM), and cannabinoids (up to 10 μM) in T24 and TCCSUP cells. We also evaluated the activation of the apoptotic cascade and whether cannabinoids have the ability to reduce invasion in T24 cells.

Results: Cannabidiol, Δ9-tetrahydrocannabinol, cannabichromene, and cannabivarin reduce cell viability of bladder cancer cell lines, and their combination with gemcitabine or cisplatin may induce differential responses, from antagonistic to additive and synergistic effects, depending on the concentrations used. Cannabidiol and Δ9-tetrahydrocannabinol were also shown to induce apoptosis via caspase-3 cleavage and reduce invasion in a Matrigel assay. Cannabidiol and Δ9-tetrahydrocannabinol also display synergistic properties with other cannabinoids like cannabichromene or cannabivarin, although individual cannabinoids may be sufficient to reduce cell viability of bladder cancer cell lines.

Discussion: Our results indicate that cannabinoids can reduce human bladder transitional cell carcinoma cell viability, and that they can potentially exert synergistic effects when combined with other agents. Our in vitro results will form the basis for future studies in vivo and in clinical trials for the development of new therapies that could be beneficial for the treatment of bladder cancer in the future.”

https://pubmed.ncbi.nlm.nih.gov/36870996/

“Our results show the ability of different cannabinoids to produce synergistic effects when combined with other agents like gemcitabine and cisplatin that are significantly different from each drug used alone.”

https://jcannabisresearch.biomedcentral.com/articles/10.1186/s42238-023-00174-z

Association between cannabis use with urological cancers: A population-based cohort study and a mendelian randomization study in the UK biobank

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“Background: Legislation of cannabis use has been approved in many European and North American countries. Its impact on urological cancers is unclear. This study was conducted to explore the association between cannabis use and the risk of urological cancers.

Methods: We identified 151,945 individuals with information on cannabis use in the UK Biobank from 2006 to 2010. Crude and age-standardized incidence ratios of different urological cancers were evaluated in the entire cohort and subgroups. Cox regression was performed for survival analysis.

Results: Previous use of cannabis was a significant protective factor for renal cell carcinoma (HR = 0.61, 95%CI:0.40-0.93, p = 0.021) and prostate cancer (HR = 0.82, 95%CI:0.73-0.93, p = 0.002) in multivariable analysis. The association between previous cannabis use and both renal cell carcinoma and bladder cancer was only observed in females (HRRCC = 0.42, 95%CI:0.19-0.94, p = 0.034; HRBCa = 0.43, 95%CI:0.21-0.86, p = 0.018) but not in men. There was no significant association between cannabis use and testicular cancer incidence. Mendelian randomization demonstrated a potential causal effect of cannabis use on a lower incidence of renal cell carcinoma.

Conclusions: Previous use of cannabis was associated with a lower risk of bladder cancer, renal cell carcinoma, and prostate cancer. The inverse association between cannabis and both renal cell carcinoma and bladder cancer was only found in females but not in males.”

https://pubmed.ncbi.nlm.nih.gov/35975633/

“Cannabis, also known as marijuana, is the most used substance derived from Cannabis Sativa which can be used for recreational or medical purposes. Some evidence also suggested that cannabinoids might induce apoptosis of cancer cells and inhibit oncogenesis, indicating a potential treatment effect”

https://onlinelibrary.wiley.com/doi/10.1002/cam4.5132

“Previous Cannabis Use Linked to Lower Risk of Some Genitourinary Cancers”

https://www.cancertherapyadvisor.com/home/cancer-topics/urologic-cancers/genitourinary-cancers-previous-cannabis-use-lower-risk/

Anti-cancer properties of cannflavin A and potential synergistic effects with gemcitabine, cisplatin, and cannabinoids in bladder cancer

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“Introduction: Several studies have shown anti-tumor effects of components present in cannabis in different models. Unfortunately, little is known about the potential anti-tumoral effects of most compounds present in cannabis in bladder cancer and how these compounds could potentially positively or negatively impact the actions of chemotherapeutic agents. Our study aims to evaluate the effects of a compound found in Cannabis sativa that has not been extensively studied to date, cannflavin A, in bladder cancer cell lines. We aimed to identify whether cannflavin A co-treatment with agents commonly used to treat bladder cancer, such as gemcitabine and cisplatin, is able to produce synergistic effects. We also evaluated whether co-treatment of cannflavin A with various cannabinoids could produce synergistic effects.

Results: Cell viability of bladder cancer cell lines was affected in a concentration-dependent fashion in response to cannflavin A, and its combination with gemcitabine or cisplatin induced differential responses-from antagonistic to additive-and synergism was also observed in some instances, depending on the concentrations and drugs used. Cannflavin A also activated apoptosis via caspase 3 cleavage and was able to reduce invasion by 50%. Interestingly, cannflavin A displayed synergistic properties with other cannabinoids like Δ9-tetrahydrocannabinol, cannabidiol, cannabichromene, and cannabivarin in the bladder cancer cell lines.

Discussion: Our results indicate that compounds from Cannabis sativa other than cannabinoids, like the flavonoid cannflavin A, can be cytotoxic to human bladder transitional carcinoma cells and that this compound can exert synergistic effects when combined with other agents. In vivo studies will be needed to confirm the activity of cannflavin A as a potential agent for bladder cancer treatment.”

https://pubmed.ncbi.nlm.nih.gov/35869542/

“A study recently demonstrated that the combination of Δ9-tetrahydrocannabinol and cannabichromene produced synergistic effects in a bladder cancer model, while another focused on the effects of cannabidiol and their potential formulation within nanoparticles to treat bladder cancer. Here, we show that other compounds from cannabis, like cannflavin A, may also induce beneficial cytotoxic and synergistic effects on bladder cancer cells. Our results also showed the ability of cannabinoids, other than Δ9-tetrahydrocannabinol, to produce synergistic effects when combined with the flavonoid cannflavin A.”

https://jcannabisresearch.biomedcentral.com/articles/10.1186/s42238-022-00151-y


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


The Role of Cannabidiol (CBD) in a Cisplatin-Induced Model of Chronic Neuropathic Pain

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“Cannabinoid-based therapies offer a safer, non-opioid alternative for the management of chronic pain. While most studies focus on the analgesic potential of the main psychoactive component of marijuana, Δ9-tetrahydrocannabinol, fewer studies have investigated the role of the non-psychoactive component, cannabidiol (CBD). CBD has been purported to have analgesic, anti-inflammatory, anticonvulsant, and anxiolytic effects. In addition to having actions at both cannabinoid receptors (CB1 and CB2 ), CBD has been shown to interact with both the transient receptor potential vanilloid-1 (TRPV1) and serotonergic (5-HT) receptors. Clinically, CBD’s lack of psychoactivity and decreased abuse liability make it an appealing pharmacotherapeutic for the management of chronic pain. Therefore, the purpose of the current study was to determine whether CBD sex- or dose-dependently reverses antinociception in an acute model of thermal pain and/or mechanical allodynia in a model of cisplatin-induced chronic neuropathic pain. Furthermore, we observed the degree to which CB1 , CB2 , 5-HT, and TRPV1 receptors may be mediating these anti-allodynic responses. Male and female wild-type mice were assessed for either the anti-allodynic effects of 0, 1, 3, 10, and 30 mg/kg CBD in a cisplatin-induced model of neuropathic pain or the antinociceptive effects of 0, 1, 3, 10, 30, and 100 mg/kg CBD in a model of acute thermal (tail-flick) pain 60 minutes following CBD administration. To determine the relative contributions of each receptor subtype in mediating the anti-allodynic effects of CBD, male and female mice were pretreated with either: vehicle, the CB1 inverse agonist SR141716A (10 mg/kg), the CB2 antagonist SR144528 (10 mg/kg), the TRPV1 antagonist capsazepine (10 mg/kg), or the 5-HT2 antagonist methysergide (4 mg/kg) 30 minutes prior to treatment with CBD. Mice were assessed for the effects of the pretreatment alone and in combination with CBD. CBD at a dose of 3 mg/kg was able to partially reverse cisplatin-induced allodynia in male and female mice, while doses of 10 and 30 mg/kg resulted in nearly complete reversal. Our preliminary findings showed that the anti-allodynic effects of 30 mg/kg CBD were completely blocked following pretreatment with SR141716A and SR144528, and partially blocked by capsazepine in both male and female mice. Interestingly, pretreatment with methysergide partially attenuated the anti-allodynic effects of CBD in females alone. In contrast, CBD (0-100 mg/kg) failed to induce antinociception on the tail-flick assay. CBD did induce mild hypothermia with males showing a greater degree of CBD-mediated hypothermia than female mice. Taken together, these findings suggest that CBD may be a more effective treatment option for the management of chronic pain. This study highlights the therapeutic potential of CBD in a model of neuropathic pain and suggests that these effects may have clinical implications for the use of cannabinoids in chronic pain management.”

https://pubmed.ncbi.nlm.nih.gov/35560789/

https://faseb.onlinelibrary.wiley.com/doi/10.1096/fasebj.2022.36.S1.R5197

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/