Cannabinoids as anticancer drugs: current status of preclinical research

Hinz, Burkhard; Ramer, Robert

doi:10.1038/s41416-022-01727-4

Cited by 81 publications

(63 citation statements)

References 158 publications

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“…Cannabinoid agonists modulate various cancer-related pathways that can lead to the blockade of the cell cycle, inhibition of the cell proliferation and cell death [ 23 ]. Cannabinoid ligands (including CBD) possess the anti-invasiveness and anti-metastatic actions [ 24 , 25 , 26 ]. Cannabinoids also exert the anti-angiogenesis effects by blocking the activation of the vascular endothelial growth factor pathway [ 27 ].…”

Section: Introductionmentioning

confidence: 99%

Cannabidiol Interacts Antagonistically with Cisplatin and Additively with Mitoxantrone in Various Melanoma Cell Lines—An Isobolographic Analysis

Marzęda

Wróblewska-Łuczka

Drozd

et al. 2022

IJMS

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The medical application of cannabidiol (CBD) has been gathering increasing attention in recent years. This non-psychotropic cannabis-derived compound possesses antiepileptic, antipsychotic, anti-inflammatory and anxiolytic properties. Recent studies report that it also exerts antineoplastic effects in multiple types of cancers, including melanoma. In this in vitro study we tried to reveal the anticancer properties of CBD in malignant melanoma cell lines (SK-MEL 28, A375, FM55P and FM55M2) administered alone, as well as in combination with mitoxantrone (MTX) or cisplatin (CDDP). The effects of CBD on the viability of melanoma cells were measured by the MTT assay; cytotoxicity was determined in the LDH test and proliferation in the BrdU test. Moreover, the safety of CBD was tested in human keratinocytes (HaCaT) in LDH and MTT tests. Results indicate that CBD reduces the viability and proliferation of melanoma-malignant cells and exerts additive interactions with MTX. Unfortunately, CBD produced antagonistic interaction when combined with CDDP. CBD does not cause significant cytotoxicity in HaCaT cell line. In conclusion, CBD may be considered as a part of melanoma multi-drug therapy when combined with MTX. A special attention should be paid to the combination of CBD with CDDP due to the antagonistic interaction observed in the studied malignant melanoma cell lines.

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Section: Introductionmentioning

confidence: 99%

Cannabidiol Interacts Antagonistically with Cisplatin and Additively with Mitoxantrone in Various Melanoma Cell Lines—An Isobolographic Analysis

Marzęda

Wróblewska-Łuczka

Drozd

et al. 2022

IJMS

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“…A number of different cannabinoids have shown antitumour effects in many preclinical studies when applied individually (for review see [1,2]). In the present study, the combination of THC and CBD showed a synergistic inhibitory effect on the viability of human glioblastoma cells at 5 µM each, and can therefore be considered as a promising add-on therapy for glioblastoma, which is in agreement with the studies of other authors [6][7][8][9][10][11].…”

Section: Discussionmentioning

confidence: 99%

“…Soon after, a growth inhibitory effect on glioma xenografts was confirmed for the selective cannabinoid receptor CB 2 agonist JWH-133 [5]. In the meantime, cannabinoid-mediated anticancer effects have also been demonstrated in a variety of other tumour entities, whereby the effects shown here range from the initially demonstrated inhibition of proliferation and induction of tumour cell apoptosis to proautophagic, anti-angiogenic, anti-invasive and antimetastatic effects (for review see [1,2]).…”

Section: Introductionmentioning

confidence: 99%

“…Over the past two decades, a large number of extensive preclinical studies have shown that cannabinoids of plant, synthetic and endogenous origin can inhibit tumourigenesis and 2 of 22 tumour spread (for review [1,2]). Studies on the effect of cannabinoids on glioma cells have been published particularly frequently, and are of great importance in that glioblastoma multiforme or astrocytoma grade IV, an extremely aggressive cancer, has a high resistance to radiation and standard chemotherapy (for review [3]).…”

Section: Introductionmentioning

confidence: 99%

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The Combination of Δ9-Tetrahydrocannabinol and Cannabidiol Suppresses Mitochondrial Respiration of Human Glioblastoma Cells via Downregulation of Specific Respiratory Chain Proteins

Rupprecht

Theisen

Wendt

et al. 2022

Cancers

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Phytocannabinoids represent a promising approach in glioblastoma therapy. Previous work has shown that a combined treatment of glioblastoma cells with submaximal effective concentrations of psychoactive Δ9-tetrahydrocannabinol (THC) and non-psychoactive cannabidiol (CBD) greatly increases cell death. In the present work, the glioblastoma cell lines U251MG and U138MG were used to investigate whether the combination of THC and CBD in a 1:1 ratio is associated with a disruption of cellular energy metabolism, and whether this is caused by affecting mitochondrial respiration. Here, the combined administration of THC and CBD (2.5 µM each) led to an inhibition of oxygen consumption rate and energy metabolism. These effects were accompanied by morphological changes to the mitochondria, a release of mitochondrial cytochrome c into the cytosol and a marked reduction in subunits of electron transport chain complexes I (NDUFA9, NDUFB8) and IV (COX2, COX4). Experiments with receptor antagonists and inhibitors showed that the degradation of NDUFA9 occurred independently of the activation of the cannabinoid receptors CB1, CB2 and TRPV1 and of usual degradation processes mediated via autophagy or the proteasomal system. In summary, the results describe a previously unknown mitochondria-targeting mechanism behind the toxic effect of THC and CBD on glioblastoma cells that should be considered in future cancer therapy, especially in combination strategies with other chemotherapeutics.

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“…As we have already mentioned, cannabinoid agonists, in addition to their analgesic, antianorexic and antiemetic effects, have shown their utility in different in vitro and in vivo models of cancer, including lung cancer [ 29 ]. The combined use of THC and powerful CBD has shown the potential to enhance these effects, also reducing the harmful effects of THC at the level of the central nervous system.…”

Section: Discussionmentioning

confidence: 99%

In Vitro Effect of Δ9-Tetrahydrocannabinol and Cannabidiol on Cancer-Associated Fibroblasts Isolated from Lung Cancer

Milián

Monleón-Guinot

Sancho‐Tello

et al. 2022

IJMS

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There is evidence that demonstrates the effect of cannabinoid agonists inhibiting relevant aspects in lung cancer, such as proliferation or epithelial-to-mesenchymal transition (EMT). Most of these studies are based on evidence observed in in vitro models developed on cancer cell lines. These studies do not consider the complexity of the tumor microenvironment (TME). One of the main components of the TME is cancer-associated fibroblasts (CAFs), cells that are relevant in the control of proliferation and metastasis in lung cancer. In this work, we evaluated the direct effects of two cannabinoid agonists, tetrahydrocannabinol (THC) and cannabidiol (CBD), used alone or in combination, on CAFs and non-tumor normal fibroblasts (NFs) isolated from adenocarcinoma or from healthy lung tissue from the same patients. We observed that these compounds decrease cell density in vitro and inhibit the increase in the relative expression of type 1 collagen (COL1A1) and fibroblast-specific protein 1 (FSP1) induced by transforming growth factor beta (TGFβ). On the other hand, we studied whether THC and CBD could modulate the interactions between CAFs or NFs and cancer cells. We conditioned the culture medium with stromal cells treated or not with THC and/or CBD and cultured A549 cells with them. We found that culture media conditioned with CAFs or NFs increased cell density, induced morphological changes consistent with EMT, inhibited cadherin-1 (CDH1) gene expression, and induced an increase in the relative expression of cadherin-2 (CDH2) and vimentin (VIM) genes in A549 cells. These changes were inhibited or decreased by THC and CBD administered alone or in combination. In another series of experiments, we conditioned culture media with A549 cells treated or not with THC and/or CBD, in the presence or absence of TGFβ. We observed that culture media conditioned with A549 in the presence of TGFβ induced an increase in the expression of COL1A1 and VIM, both in CAFs and in non-tumor NFs. Both THC and CBD ameliorated these effects. In summary, the results presented here reinforce the usefulness of cannabinoid agonists for the treatment of some relevant aspects of lung cancer pathology, and demonstrate in a novel way their possible effects on CAFs as a result of their relationship with cancer cells. Likewise, the results reinforce the usefulness of the combined use of THC and CBD, which has important advantages in relation to the possibility of using lower doses, thus minimizing the psychoactive effects of THC.

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Cannabinoids as anticancer drugs: current status of preclinical research

Cited by 81 publications

References 158 publications

Cannabidiol Interacts Antagonistically with Cisplatin and Additively with Mitoxantrone in Various Melanoma Cell Lines—An Isobolographic Analysis

Cannabidiol Interacts Antagonistically with Cisplatin and Additively with Mitoxantrone in Various Melanoma Cell Lines—An Isobolographic Analysis

The Combination of Δ9-Tetrahydrocannabinol and Cannabidiol Suppresses Mitochondrial Respiration of Human Glioblastoma Cells via Downregulation of Specific Respiratory Chain Proteins

In Vitro Effect of Δ9-Tetrahydrocannabinol and Cannabidiol on Cancer-Associated Fibroblasts Isolated from Lung Cancer

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