Category Archives: Cancer

Cannabidiol inhibits invasion and metastasis in colorectal cancer cells by reversing epithelial-mesenchymal transition through the Wnt/β-catenin signaling pathway

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“Colorectal cancer (CRC) is the leading cause of cancer deaths worldwide, wherein distant metastasis is the main reason for death. The non-psychoactive phytocannabinoid cannabidiol (CBD) effectively induces the apoptosis of CRC cells. We investigated the role of CBD in the migration and metastasis of CRC cells.

CBD significantly inhibited proliferation, migration, and invasion of colon cancer cells in a dose- or time-dependent manner. CBD could also inhibit epithelial-mesenchymal transition (EMT) by upregulating epithelial markers such as E-cadherin and downregulating mesenchymal markers such as N-cadherin, Snail, Vimentin, and HIF-1α. CBD could suppress the activation of the Wnt/β-catenin signaling pathway, inhibit the expression of β-catenin target genes such as APC and CK1, and increase the expression of Axin1. Compared to the control group, the volume and weight of orthotopic xenograft tumors significantly decreased after the CBD treatment.

The results demonstrated that CBD inhibits invasion and metastasis in CRC cells. This was the first study elucidating the underlying molecular mechanism of CBD in inhibiting EMT and metastasis via the Wnt/β-catenin signaling pathway in CRC cells. The molecular mechanism by which CBD inhibits EMT and metastasis of CRC cells was shown to be through the Wnt/β-catenin signaling pathway for the first time.”

https://pubmed.ncbi.nlm.nih.gov/35960375/

https://link.springer.com/article/10.1007/s00432-022-04265-x

Medical Marijuana Use for Cancer-Related Symptoms among Floridians: A Descriptive Study

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“Background: Thirty-six states, including Florida, have legalized marijuana for medical and/or recreational use, yet how it is used and perceived by persons with cancer is not well understood. 

Objectives: The purpose of this study was to identify patterns of use, perceived benefits, and side effects of medical marijuana (MMJ) among cancer patients in Florida. 

Methods: For this descriptive, cross-sectional study, anyone residing within the state of Florida who was diagnosed or treated for a malignancy within the last five years and had used MMJ was eligible. An online survey containing questions about dosing, side effects, perceived benefits, and barriers to use was used. Descriptive statistics including frequencies, percentages, means, and standard deviations were used to analyze quantitative data. Responses to open-ended questions were coded and categorized. 

Results: Sleep (n = 112), pain (n = 96), and anxiety (n = 82) were the most common symptoms participants used MMJ to relieve and overall felt it was highly effective. MMJ was well tolerated with a minority (10.3%) reporting any adverse effects. Cost was the most frequent barrier reported by participants (42.8%). A variety of legal, bureaucratic, and system-related barriers were described. 

Conclusion: Participants perceived MMJ to be helpful in alleviating cancer symptoms. They held negative perceptions of the way MMJ is implemented and integrated into their oncology treatment plan. Enhanced communication and patient/provider education on MMJ are needed to inform patient decision making.”

https://pubmed.ncbi.nlm.nih.gov/35960820/

https://www.liebertpub.com/doi/10.1089/jpm.2022.0100

Effect of CB2 Stimulation on Gene Expression in Pediatric B-Acute Lymphoblastic Leukemia: New Possible Targets

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“Acute lymphoblastic leukemia type B (B-ALL) is the most common kind of pediatric leukemia, characterized by the clonal proliferation of type B lymphoid stem cells. Important progress in ALL treatments led to improvements in long-term survival; nevertheless, many adverse long-term consequences still concern the medical community. Molecular and cellular target therapies, together with immunotherapy, are promising strategies to overcome these concerns.

Cannabinoids, enzymes involved in their metabolism, and cannabinoid receptors type 1 (CB1) and type 2 (CB2) constitute the endocannabinoid system, involved in inflammation, immune response, and cancer. CB2 receptor stimulation exerts anti-proliferative and anti-invasive effects in many tumors.

In this study, we evaluated the effects of CB2 stimulation on B-ALL cell lines, SUP-B15, by RNA sequencing, Western blotting, and ELISA. We observe a lower expression of CB2 in SUP-B15 cells compared to lymphocytes from healthy subjects, hypothesizing its involvement in B-ALL pathogenesis. CB2 stimulation reduces the expression of CD9, SEC61G, TBX21, and TMSB4X genes involved in tumor growth and progression, and also negatively affects downstream intracellular pathways.

Our findings suggest an antitumor role of CB2 stimulation in B-ALL, and highlight a functional correlation between CB2 receptors and specific anti-tumoral pathways, even though further investigations are needed.”

https://pubmed.ncbi.nlm.nih.gov/35955786/

“The antineoplastic role of cannabinoids in malignancy of the immune system, as well as in many other tumors, i.e., osteosarcoma, is well documented. Cannabinoids derive from the Cannabis plant, and interact with the cannabinoid receptors CB1 and CB2, principally expressed in the central nervous system and in peripheral and immune cells, respectively. These receptors, together with their specific ligands (endocannabinoids) and the enzymes involved in their own synthesis and degradation, constitute the endocannabinoid system (ECS). ECS is involved in many biological functions, such as pain management, regulation of appetite, control of bone metabolism, and, noteworthily, it modulates both inflammatory processes and immune response. Several authors proposed ECS as anticancer target for different neoplasms; in particular, a proper stimulation of CB2 receptors is responsible for counteracting tumor growth and progression. We demonstrate the involvement of ECS in this neoplasm and highlight the possibility to target it to arrest growth and progression of B-ALL

Our findings describe the involvement of CB2 receptors in the pathogenesis of B-ALL, and also propose its stimulation as an innovative and effective anticancer strategy. In particular, this approach is a “molecular target therapy approach”, since the selective triggering of cannabinoid modulates both gene and protein expression. We identified a specific anti-tumoral signature playing a key role in the development and maintenance of tumors, speculating a protective effect of CB2 selective stimulation. Certainly, further investigations are needed to better understand the molecular and biochemical mechanisms underlying the observed interactions, but our study seems to already highlight a good and beneficial therapeutic perspective to ameliorate the outcome for high-risk B-ALL patients.”

https://www.mdpi.com/1422-0067/23/15/8651/htm

An Examination of the Anti-Cancer Properties of Plant Cannabinoids in Preclinical Models of Mesothelioma

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“Mesothelioma is an aggressive cancer with limited treatment options and a poor prognosis. Phytocannabinoids possess anti-tumour and palliative properties in multiple cancers, however their effects in mesothelioma are unknown. We investigated the anti-cancer effects and potential mechanisms of action for several phytocannabinoids in mesothelioma cell lines.

A panel of 13 phytocannabinoids inhibited growth of human (MSTO and H2452) and rat (II-45) mesothelioma cells in vitro, and cannabidiol (CBD) and cannabigerol (CBG) were the most potent compounds. Treatment with CBD or CBG resulted in G0/G1 arrest, delayed entry into S phase and induced apoptosis. CBD and CBG also significantly reduced mesothelioma cell migration and invasion. These effects were supported by changes in the expression of genes associated with the cell cycle, proliferation, and cell movement following CBD or CBG treatment. Gene expression levels of CNR1, GPR55, and 5HT1A also increased with CBD or CBG treatment. However, treatment with CBD or CBG in a syngeneic orthotopic rat mesothelioma model was unable to increase survival.

Our data show that cannabinoids have anti-cancer effects on mesothelioma cells in vitro and alternatives of drug delivery may be needed to enhance their effects in vivo.”

https://pubmed.ncbi.nlm.nih.gov/35954477/

We showed that several phytocannabinoids inhibited growth of mesothelioma cells, with two phytocannabinoids, cannabidiol (CBD) and cannabigerol (CBG), being the most potent. CBD and CBG also inhibited mesothelioma cell migration and invasion. Gene expression analysis highlighted signalling pathways that play a role in how CBD and CBG may exert their anti-cancer effects. CBD and CBG were unable to increase survival in a rat model of mesothelioma but this may be due to limitations in the drug delivery method.

Our data present the first report that plant cannabinoids have anti-proliferative effects on mesothelioma cells, that was associated with apoptosis, rather than autophagy or production of ROS. CBD and CBG were the most potent cannabinoids and also inhibited mesothelioma cell migration and invasion.”

https://www.mdpi.com/2072-6694/14/15/3813/htm

Antitumor Effects of Cannabinoids in Human Pancreatic Ductal Adenocarcinoma Cell Line (Capan-2)-Derived Xenograft Mouse Model

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“Background: Pancreatic cancer is considered a rare type of cancer, but the mortality rate is high. Cannabinoids extracted from the cannabis plant have been interested as an alternative treatment in cancer patients. Only a few studies are available on the antitumor effects of cannabinoids in pancreatic cancer. Therefore, this study aims to evaluate the antitumor effects of cannabinoids in pancreatic cancer xenografted mouse model.

Materials and methods: Twenty-five nude mice were subcutaneously transplanted with a human pancreatic ductal adenocarcinoma cell line (Capan-2). All mice were randomly assigned into 5 groups including negative control (gavage with sesame oil), positive control (5 mg/kg 5-fluorouracil intraperitoneal administration), and cannabinoids groups that daily received THC:CBD, 1:6 at 1, 5, or 10 mg/kg body weight for 30 days, respectively. Xenograft tumors and internal organs were collected for histopathological examination and immunohistochemistry.

Results: The average tumor volume was increased in all groups with no significant difference. The average apoptotic cells and caspase-3 positive cells were significantly increased in cannabinoid groups compared with the negative control group. The expression score of proliferating cell nuclear antigen in positive control and cannabinoids groups was decreased compared with the negative control group.

Conclusions: Cannabinoids have an antitumor effect on the Capan-2-derived xenograft mouse model though induce apoptosis and inhibit proliferation of tumor cells in a dose-dependent manner.”

https://pubmed.ncbi.nlm.nih.gov/35937289/

“In conclusion, cannabinoid treatment in mice was not affected by weight gain and blood profiles. It can induce apoptosis and inhibit the proliferation of human pancreatic ductal adenocarcinoma cells in a dose-dependent manner. This study suggested that cannabinoids have an antitumor effect on a human pancreatic ductal adenocarcinoma cell line (Capan-2)-derived xenograft mouse model.”

https://www.frontiersin.org/articles/10.3389/fvets.2022.867575/full


Oral cannabidiol for prevention of acute and transient chemotherapy-induced peripheral neuropathy

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“Purpose: To assess the safety, dosing, and preventive effects of cannabidiol (CBD) on chemotherapy-induced peripheral neuropathy (CIPN) in patients receiving oxaliplatin- or paclitaxel-based chemotherapy.

Methods: Patients with cancer scheduled to undergo treatment with carboplatin and paclitaxel (Carbo-Tax) or capecitabine and oxaliplatin (CAPOX) received 150 mg CBD oil twice daily (300 mg/daily) for 8 days beginning 1 day before initiation of chemotherapy. Ten CIPN-specific patient-reported outcome (PRO) measures were captured at baseline and each day after the first cycle of chemotherapy for 8 days. Multi-frequency vibrometry (MF-V) was captured at baseline and day 4 ± 1 after initiation of chemotherapy. Controls were obtained from a similar patient cohort that did not receive CBD. Adverse events were captured using the CTCAE ver. 4.03.

Results: From March to December 2021, 54 patients were recruited. CBD-treated patients were significantly older (p = 0.013/0.037, CAPOX/Carbo-Tax) compared to controls. Patients receiving CBD and CAPOX or Carbo-Tax showed significantly lower (better) change in Z-scores in high-frequency MF-V (125 and 250 Hz) compared to controls. This difference was most pronounced for patients receiving Carbo-Tax (- 1.76, CI-95 = [- 2.52; – 1.02] at 250 Hz). CAPOX patients treated with CBD had significantly lower peak baseline-adjusted difference in three PRO items on cold sensitivity to touch, discomfort swallowing cold liquids, and throat discomfort (- 2.08, – 2.06, and – 1.81, CI-95 = [- 3.89; – 0.12], NRS 0-10). No significant differences in PRO items were found for patients receiving Carbo-Tax. Possible side effects included stomach pain (grades 1-2) for patients receiving CAPOX.

Conclusion: CBD attenuated early symptoms of CIPN with no major safety concerns. Long-term follow-up is ongoing. Results should be confirmed in a larger, randomized study.”

https://pubmed.ncbi.nlm.nih.gov/35933415/

https://link.springer.com/article/10.1007/s00520-022-07312-y

Cannabigerol (CBG) attenuates mechanical hypersensitivity elicited by chemotherapy-induced peripheral neuropathy

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“Background: Cannabigerol (CBG) is a non-psychoactive phytocannabinoid produced by the plant Cannabis sativa with affinity to various receptors involved in nociception. As a result, CBG is marketed as an over-the-counter treatment for many forms of pain. However, there is very little research-based evidence for the efficacy of CBG as an anti-nociceptive agent.

Methods: To begin to fill this knowledge gap, we assessed the anti-nociceptive effects of CBG in C57BL/6 mice using three different models of pain; cisplatin-induced peripheral neuropathy, the formalin test, and the tail-flick assay.

Results: Using the von Frey test, we found that CBG attenuated mechanical hypersensitivity evoked by cisplatin-induced peripheral neuropathy in both male and female mice. Additionally, we observed that this CBG-induced reduction in mechanical hypersensitivity was attenuated by the α2 -adrenergic receptor antagonist atipamezole (3 mg/kg, i.p.) and the CB1 R antagonist, AM4113 (3 mg/kg, i.p.), and blocked by the CB2 R antagonist/inverse agonist, SR144528 (10 mg/kg, i.p.). We found that the TRPV1 antagonist, SB705498 (20 mg/kg, i.p.) was unable to prevent CBG actions. Furthermore, we show that CBG:CBD oil (10 mg/kg, i.p.) was more effective than pure CBG (10 mg/kg) at reducing mechanical hypersensitivity in neuropathic mice. Lastly, we show that pure CBG and CBG:CBD oil were ineffective at reducing nociception in other models of pain, including the formalin and tail flick assays.

Conclusions: Our findings support the role of CBG in alleviating mechanical hypersensitivity evoked by cisplatin-induced peripheral neuropathy, but highlight that these effects may be limited to specific types of pain.”

https://pubmed.ncbi.nlm.nih.gov/35899583/

https://onlinelibrary.wiley.com/doi/10.1002/ejp.2016

Anti-Tumorigenic Effect of a Novel Derivative of 2-Hydroxyoleic Acid and the Endocannabinoid Anandamide on Neuroblastoma Cells

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“Modulation of the endogenous cannabinoid system has been suggested as a potential anticancer strategy.

In the search for novel and less toxic therapeutic options, structural modifications of the endocannabinoid anandamide and the synthetic derivative of oleic acid, Minerval (HU-600), were done to obtain 2-hydroxy oleic acid ethanolamide (HU-585), which is an HU-600 derivative with the anandamide side chain.

We showed that treatment of SK-N-SH neuroblastoma cells with HU-585 induced a better anti-tumorigenic effect in comparison to HU-600 as evidenced by 3-[4,5-dimethylthiazole-2-yl]-2,5-diphenyltetrazolium bromide assay, colony-forming assay, and migration assay. Moreover, HU-585 demonstrated pro-apoptotic properties shown by increased levels of activated caspase-3 following treatment and a better senescence induction effect in comparison to HU-600, as demonstrated by increased activity of lysosomal β-galactosidase. Finally, we observed that combined treatment of HU-585 with the senolytic drugs ABT-263 in vitro, and ABT-737 in vivo resulted in enhanced anti-proliferative effects and reduced neuroblastoma xenograft growth in comparison to treatment with HU-585 alone.

Based on these results, we suggest that HU-585 is a pro-apoptotic and senescence-inducing compound, better than HU-600. Hence, it may be a beneficial option for the treatment of resistant neuroblastoma especially when combined with senolytic drugs that enhance its anti-tumorigenic effects.”

https://pubmed.ncbi.nlm.nih.gov/35884854/

“The cannabinoids are a group of more than 100 chemically related compounds found in the marijuana plant Cannabis sativa, that have been found to possess diverse pharmacological activities in cancer, including cytostatic, apoptotic, and antiangiogenic effects. Tetrahydrocannabinol (THC), the main psychoactive constituent in Cannabis sativa, acts mainly through the activation of specific cannabinoid receptors CB1 and CB2 and thus mimics the binding of the animal endogenous cannabinoids (named endocannabinoids).”

https://www.mdpi.com/2227-9059/10/7/1552/htm

Improved Therapeutic Efficacy of CBD with Good Tolerance in the Treatment of Breast Cancer through Nanoencapsulation and in Combination with 20(S)-Protopanaxadiol (PPD)

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“Cannabidiol (CBD), a nonpsychoactive major component derived from Cannabis sativa, widely used in neurodegenerative diseases, has now been proven to have growth inhibitory effects on many tumor cell lines, including breast tumors. Meanwhile CBD can effectively alleviate cancer-associated pain, anxiety, and depression, especially tumor cachexia, thus it is very promising as an anti-tumor drug with unique advantages.

20(S)-Protopanaxadiol (PPD) derived from the best-known tonic Chinese herbal medicine Ginseng was designed to be co-loaded with CBD into liposomes to examine their synergistic tumor-inhibitory effect. The CBD-PPD co-loading liposomes (CP-liposomes) presented a mean particle size of 138.8 nm. Further glycosyl-modified CP-liposomes (GMCP-liposomes) were prepared by the incorporation of n-Dodecyl β-D-maltoside (Mal) into the liposomal bilayer with glucose residue anchored on the surface to act as a ligand targeting the GLUT1 receptor highly expressed on tumor cells.

In vivo studies on murine breast tumor (4T1 cells)-bearing BALB/c mice demonstrated good dose dependent anti-tumor efficacy of CP-liposomes. A high tumor inhibition rate (TIR) of 82.2% was achieved with good tolerance. However, glycosylation modification failed to significantly enhance TIR of CP-liposomes.

In summary, combined therapy with PPD proved to be a promising strategy for CBD to be developed into a novel antitumor drug, with characteristics of effectiveness, good tolerance, and the potential to overcome tumor cachexia.”

https://pubmed.ncbi.nlm.nih.gov/35893789/

https://www.mdpi.com/1999-4923/14/8/1533/htm

Cannabidiol Regulates PPARγ-Dependent Vesicle Formation as well as Cell Death in A549 Human Lung Cancer Cells

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“Extracts of phytocannabinoids from Cannabis sativa have been studied for therapeutic purposes. Although nonpsychoactive CBD has been studied as a promising anticancer drug because it induces apoptosis in many cancer cells, it is also known to induce several physiological changes.

In this study, we clarify the functional role it plays in the morphological characteristics of intracellular vesicle formation as well as apoptosis in A549 human lung cancer cells.

CBD treatment shows growth inhibition at concentrations above 20 μM, but FACS analysis shows low efficacy in terms of cell death. Microscopic observations suggest that multiple vesicles were detected in the cytoplasmic region of CBD-treated A549 cells.

CBD treatment upregulates apoptosis-related proteins, such as p53, PARP, RIP1, RIP3, Atg12, and Beclin, indicating that CBD regulates several types of cell death. CBD treatment also induced E-cadherin, PPARγ, clathrin, β-adaptin, and Tsg101, also known to be cellular-differentiation inducers or vesicle-formation components.

Treatment combining CBD with GW9662, a PPARγ inhibitor, reduced CBD-induced cytoplasmic vesicle formation. This indicates that PPARγ regulates the vesicle-formation mechanism. However, CBD-treated E-cad KO clones did not show this regulatory mechanism.

These results elucidate the pharmacological and molecular networks associated with CBD in PPARγ-dependent vesicle formation and the induction of apoptosis.”

https://pubmed.ncbi.nlm.nih.gov/35890134/

“Recently, the pharmacological efficacy of CBD has been focused on in many types of disease models. In this study, we have shown that CBD treatment upregulated cell death proteins, such as p53, PARP, RIP1, RIP3, Atg12, and Beclin. In addition, CBD treatment also induced E-cadherin, PPARγ, clathrin, β-adaptin, and Tsg101, also known to be cellular-differentiation inducers or vesicle-formation components.

We have also shown that PPARγ regulates the vesicle-formation mechanism. Therefore, not only have we confirmed cell death induction by CBD, we have also confirmed the regulation of vesicle formation by PPARγ in various cancer models.

Detailed molecuclar insights would enhance the therapeutic utilization of CBD without side effects. Cellular proliferation and death could be determined by a variety of molecular regulations in cellular networks composed of a variety of proteins. Moreover, the physiological changes in cells will be closely related to functional changes in intracellular organelles.

We suggest that an understanding of the complex intracellular network system is necessary to optimize the pharmacological efficacy of CBD. These steady research efforts will make significant progress in increasing the utilization of CBD, which has been restricted by legal regulations in some countries.”

https://www.mdpi.com/1424-8247/15/7/836/htm