Molecular Mechanisms Involved in the Antitumor Activity of Cannabinoids on Gliomas: Role for Oxidative Stress

Massi, Paola; Valenti, Marta; Solinas, M.; Parolaro, Daniela

doi:10.3390/cancers2021013

Cited by 27 publications

(19 citation statements)

References 59 publications

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“…1a). On the other hand, CBD (20 μM) treatment induced oxidative stress 15,27 that was accompanied by strong activation of Jun N-terminal Kinase 1/2 (JNK1/2) and followed by a notable increase in BECLIN-1 levels (an upstream protein of the autophagic cascade) in U87MG cells (Fig. 1a).…”

Section: Cbd-mediated Upregulation Of Autophagy In a 2d Culture Of U8mentioning

confidence: 99%

“…Non-psychogenic CBD, a powerful inducer of intracellular oxidative stress 15,27 , was previously demonstrated as an initiator of both apoptotic and autophagic signaling pathways in several types of cancer cells including GBM 12,[28][29][30] . A challenging problem is to further elucidate interference between apoptosis and autophagy during GBM cell death (especially, using of 3D GBM cultures) to find optimal and safe conditions for cancer treatment.…”

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confidence: 99%

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RETRACTED ARTICLE: Inhibition of autophagic flux differently modulates cannabidiol-induced death in 2D and 3D glioblastoma cell cultures

Ivanov

Grabham

et al. 2020

Sci Rep

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Radiotherapy combined with chemotherapy is the major treatment modality for human glioblastoma multiforme (GBM). GBMs eventually relapse after treatment and the average survival of GBM patients is less than two years. There is some evidence that cannabidiol (CBD) can induce cell death and increases the radiosensitivity of GBM by enhancing apoptosis. Beside initiation of death, CBD has been demonstrated as an inducer of autophagy. In the present study, we address the question whether CBD simultaneously induces a protective effect in GBM by upregulating autophagy. Addition of chloroquine that suppressed autophagic flux to 2D GBM cultures increased CBD-induced cell death, presenting proof for the protective autophagy. Blockage of autophagy upregulated radiation-induced cytotoxicity but only modestly affected the levels of cell death in CBD-or CBD/γ-irradiated 3D GBM cultures. Furthermore, CBD enhanced the pro-apoptotic activities of JNK1/2 and MAPK p38 signaling cascades while partially downregulated the pro-survival PI3K-AKT cascade, thereby changing a balance between cell death and survival. Suppression of JNK activation partially reduced CBD-induced cell death in 3D GBM cultures. In contrast, co-treatment of CBD-targeted cells with inhibitors of PI3K-AKT-NF-κB, IKK-NF-κB or JAK2-STAT3 pathways killed surviving GBM cells in both 2D and 3D cultures, potentially improving the therapeutic ratio of GBM. Human glioblastoma multiforme (GBM) is the most lethal primary brain cancer in adults. In the United States alone, approximately 12,000 patients are diagnosed with GBM each year 1. The standard care for GBM includes surgical resection followed by concurrent external beam radiotherapy (with a total dose of 60 Gy) together with temozolomide (TMZ), as a supplemental DNA-methylating agent. It is followed by one year of adjuvant treatment with TMZ 2. While external beam radiation therapy efficiently targets brain tumors, it could be accompanied by severe side effects, such as encephalopathy, strong cognitive and memory deficits 3-8. Despite advances in GBM radiotherapy, outcomes remain poor with a median survival rate of 12-15 months after initial diagnosis 9,10. In the past 10 years, survival in the treatment of this disease did not increase significantly. In spite of intense investigation on the gene drivers of GBM tumorigenesis, targeted therapies against these drivers have remained inefficient 11. Numerous studies in the recent years revealed pronounced cytotoxic effects of cannabinoids [cannabidiol (CBD) and Δ 9-tetrahydrocannabinol (THC)] for GBM in cell culture and experimental animals 12-16. Furthermore, preclinical studies demonstrated that treatment of GBM by combinations of cannabinoids and γ-irradiation or cannabinoids with TMZ was more effective against cancer cells than non-transformed cells in the brain 17-19. To further increase efficiency, specificity, and safety of the treatment, we address in the present study the question whether autophagy could play a protective role in the survival of CBD/γ-irradiation...

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Section: Cbd-mediated Upregulation Of Autophagy In a 2d Culture Of U8mentioning

confidence: 99%

mentioning

confidence: 99%

RETRACTED ARTICLE: Inhibition of autophagic flux differently modulates cannabidiol-induced death in 2D and 3D glioblastoma cell cultures

Ivanov

Grabham

et al. 2020

Sci Rep

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“…In addition, cannabinoids activated the intrinsic apoptosis pathway after an increase of ceramide which, in turn, inhibited the PI3K/Akt and Raf1/MEK/ERK pro-survival pathways, thereby allowing BAD to translocate to the mitochondria. CBs were also shown to trigger apoptosis via ceramide-mediated cell death and via oxidative stress [112]. Specifically, in glioma cells, CBD led to a production of reactive oxygen species (ROS), glutathione (GSH) depletion, and caspase-9, -8, and -3 activation.…”

Section: Brain Cancermentioning

confidence: 99%

The Endocannabinoid System: A Target for Cancer Treatment

Laezza

Pagano

Navarra

et al. 2020

IJMS

108

119

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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.

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“…Some glioblastoma patients currently use cannabidiol, based on preclinical studies [198-200], internet chatroom discussions, and anecdotal reports of benefit. In a formal study of cannabidiol, much of the in vitro anti-cancer and specifically anti-glioma effects derive from its 5-LO inhibition.…”

Section: Introductionmentioning

confidence: 99%

“…As mentioned above, ketaconazole more than doubles CSF ritonavir levels (2.4 to 6.6 ng/mL) in HIV positive people [173]. Concomitant administration of ritonavir (400 mg twice daily) plus ketoconazole [200 mg twice daily] was well tolerated and resulted a in disproportionate increase in CSF ritonavir level compared to a small increase in plasma level [173]. Both drugs, ritonavir and ketoconazole, as well as itraconazole, are substrates for and inhibitors of p-gp and MRP1.…”

Section: Introductionmentioning

confidence: 99%

CUSP9* treatment protocol for recurrent glioblastoma: aprepitant, artesunate, auranofin, captopril, celecoxib, disulfiram, itraconazole, ritonavir, sertraline augmenting continuous low dose temozolomide

Kast¹,

2014

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CUSP9 treatment protocol for recurrent glioblastoma was published one year ago. We now present a slight modification, designated CUSP9*. CUSP9* drugs- aprepitant, artesunate, auranofin, captopril, celecoxib, disulfiram, itraconazole, sertraline, ritonavir, are all widely approved by regulatory authorities, marketed for non-cancer indications. Each drug inhibits one or more important growth-enhancing pathways used by glioblastoma. By blocking survival paths, the aim is to render temozolomide, the current standard cytotoxic drug used in primary glioblastoma treatment, more effective. Although esthetically unpleasing to use so many drugs at once, the closely similar drugs of the original CUSP9 used together have been well-tolerated when given on a compassionate-use basis in the cases that have come to our attention so far. We expect similarly good tolerability for CUSP9*. The combined action of this suite of drugs blocks signaling at, or the activity of, AKT phosphorylation, aldehyde dehydrogenase, angiotensin converting enzyme, carbonic anhydrase -2,- 9, -12, cyclooxygenase-1 and -2, cathepsin B, Hedgehog, interleukin-6, 5-lipoxygenase, matrix metalloproteinase -2 and -9, mammalian target of rapamycin, neurokinin-1, p-gp efflux pump, thioredoxin reductase, tissue factor, 20 kDa translationally controlled tumor protein, and vascular endothelial growth factor. We believe that given the current prognosis after a glioblastoma has recurred, a trial of CUSP9* is warranted.

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Molecular Mechanisms Involved in the Antitumor Activity of Cannabinoids on Gliomas: Role for Oxidative Stress

Cited by 27 publications

References 59 publications

RETRACTED ARTICLE: Inhibition of autophagic flux differently modulates cannabidiol-induced death in 2D and 3D glioblastoma cell cultures

RETRACTED ARTICLE: Inhibition of autophagic flux differently modulates cannabidiol-induced death in 2D and 3D glioblastoma cell cultures

The Endocannabinoid System: A Target for Cancer Treatment

CUSP9* treatment protocol for recurrent glioblastoma: aprepitant, artesunate, auranofin, captopril, celecoxib, disulfiram, itraconazole, ritonavir, sertraline augmenting continuous low dose temozolomide

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