Cannabinoid WIN 55,212-2 Inhibits Human Glioma Cell Growth by Triggering ROS-Mediated Signal Pathways

Wang, Kun; Wang, Qian; Li, Qinghao; Zhang, Zhaoqiang; Gao, Jing; Fan, Cundong; Sun, Bo; Ni, Qingbin

doi:10.1155/2021/6612592

Cited by 8 publications

(11 citation statements)

References 36 publications

(44 reference statements)

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“…Several natural or synthetical compounds have been reported to induce anti-glioma effect via ROS-dependent mechanism. WIN 55,212-2, a cannabinoid analogue, dose-dependently inhibits glioma cell proliferation, migration, and invasion in vitro , effectively suppresses glioma spheroids growth ex vivo ( 42 ). WIN 55,212-2 also induces significant apoptosis, and causes dysfunction of VEGF-AKT/FAK signaling ( 42 ).…”

Section: Discussionmentioning

confidence: 99%

“…WIN 55,212-2, a cannabinoid analogue, dose-dependently inhibits glioma cell proliferation, migration, and invasion in vitro , effectively suppresses glioma spheroids growth ex vivo ( 42 ). WIN 55,212-2 also induces significant apoptosis, and causes dysfunction of VEGF-AKT/FAK signaling ( 42 ). The effects of WIN 55,212-2 are ROS-dependent, ROS inhibition effectively attenuates dysfunction of VEGF-AKT/FAK signaling and eventually improves glioma cell proliferation, migration, and invasion ( 42 ).…”

Section: Discussionmentioning

confidence: 99%

“…WIN 55,212-2 also induces significant apoptosis, and causes dysfunction of VEGF-AKT/FAK signaling ( 42 ). The effects of WIN 55,212-2 are ROS-dependent, ROS inhibition effectively attenuates dysfunction of VEGF-AKT/FAK signaling and eventually improves glioma cell proliferation, migration, and invasion ( 42 ). Osthole, a coumarin derivative, is found to trigger glioma cell necroptosis accompanied with ROS production ( 43 ).. Osthole treatment decreases the expression of necroptosis inhibitor caspase-8, and the levels of necroptosis proteins receptor-interacting protein 1 (RIP1), RIP3 and mixed lineage kinase domain-like protein ( 43 ).…”

Section: Discussionmentioning

confidence: 99%

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LCS-1 inhibition of superoxide dismutase 1 induces ROS-dependent death of glioma cells and degradates PARP and BRCA1

et al. 2022

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Gliomas are characterized by high morbidity and mortality, and have only slightly increased survival with recent considerable improvements for treatment. An innovative therapeutic strategy had been developed via inducing ROS-dependent cell death by targeting antioxidant proteins. In this study, we found that glioma tissues expressed high levels of superoxide dismutase 1 (SOD1). The expression of SOD1 was upregulated in glioma grade III and V tissues compared with that in normal brain tissues or glioma grade I tissues. U251 and U87 glioma cells expressed high levels of SOD1, low levels of SOD2 and very low levels of SOD3. LCS-1, an inhibitor of SOD1, increased the expression SOD1 at both mRNA and protein levels slightly but significantly. As expected, LCS-1 caused ROS production in a dose- and time-dependent manner. SOD1 inhibition also induced the gene expression of HO-1, GCLC, GCLM and NQO1 which are targeting genes of nuclear factor erythroid 2-related factor 2, suggesting the activation of ROS signal pathway. Importantly, LCS-1 induced death of U251 and U87 cells dose- and time-dependently. The cell death was reversed by the pretreatment of cells with ROS scavenges NAC or GSH. Furthermore, LCS-1 decreased the growth of xenograft tumors formed by U87 glioma cells in nude mice. Mechanistically, the inhibition of P53, caspases did not reverse LCS-1-induced cell death, indicating the failure of these molecules involving in cell death. Moreover, we found that LCS-1 treatment induced the degradation of both PARP and BRCA1 simultaneously, suggesting that LCS-1-induced cell death may be associated with the failure of DNA damage repair. Taking together, these results suggest that the degradation of both PARP and BRCA1 may contribute to cell death induced by SOD1 inhibition, and SOD1 may be a target for glioma therapy.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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LCS-1 inhibition of superoxide dismutase 1 induces ROS-dependent death of glioma cells and degradates PARP and BRCA1

et al. 2022

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“…Consequently, the Akt substrate mechanistic (formerly “mammalian”) target of rapamycin complex 1 (mTORC1) is inhibited, thereby leading to the stimulation of autophagy (the process of cell “self‐digestion”) and, in turn, of a mitochondrial damage‐mediated pro‐apoptotic response (Cudaback et al, 2010 ; Salazar et al, 2009 ). This process of glioma cell death may be accompanied by other CB 1 R/CB 2 R‐evoked cell growth‐inhibiting mechanisms such as the induction of oxidative stress, the blockade of the G1/S cell‐cycle transition, and the regulation of the transcription factor Krox24/Egr1 (Bouaboula et al, 1995 ; Dumitru et al, 2018 ; Ellert‐Miklaszewska et al, 2020 ; Krones‐Herzig et al, 2005 ; Wang et al, 2021 ). Additional mechanisms, including the inhibition of angiogenesis (Blázquez et al, 2003 ) and invasiveness (Blázquez et al, 2008 ; Ramer & Hinz, 2008 ), can also contribute to the observed CB 1 R/CB 2 R‐induced impairment of glioma growth in mouse models (see below).…”

Section: Cannabinoid‐evoked Growth‐inhibiting Effects In Glioma Cellsmentioning

confidence: 99%

Endocannabinoid signaling in glioma

Costas-Insua

Guzmán

2022

Glia

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High-grade gliomas constitute the most frequent and aggressive form of primary brain cancer in adults. These tumors express cannabinoid CB 1 and CB 2 receptors, as well as other elements of the endocannabinoid system. Accruing preclinical evidence supports that pharmacological activation of cannabinoid receptors located on glioma cells exerts overt anti-tumoral effects by modulating key intracellular signaling pathways. The mechanism of this cannabinoid receptor-evoked anti-tumoral activity in experimental models of glioma is intricate and may involve an inhibition not only of cancer cell survival/proliferation, but also of invasiveness, angiogenesis, and the stem cell-like properties of cancer cells, thereby affecting the complex tumor microenvironment. However, the precise biological role of the endocannabinoid system in the generation and progression of glioma seems very context-dependent and remains largely unknown. Increasing our basic knowledge on how (endo)cannabinoids act on glioma cells could help to optimize experimental cannabinoid-based anti-tumoral therapies, as well as the preliminary clinical testing that is currently underway.

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“…Moreover, cannabidiol (CBD) augments the cytotoxic effects of anti-cancer drugs for treatment of head and neck squamous cell carcinoma via apoptosis and autophagy [ 16 ]. A recent study also showed that the synthetic cannabinoid WIN-55,212-2 exerts anti-proliferative actions in human glioma cells through reactive oxygen species (ROS) induction [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

Non-Canonical Cannabinoid Receptors with Distinct Binding and Signaling Properties in Prostate and Other Cancer Cell Types Mediate Cell Death

Shoeib

Benson

et al. 2022

IJMS

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Cannabinoids exert anti-cancer actions; however, the underlying cytotoxic mechanisms and the cannabinoid receptors (CBRs) involved remain unclear. In this study, CBRs were characterized in several cancer cell lines. Radioligand binding screens surprisingly revealed specific binding only for the non-selective cannabinoid [3H]WIN-55,212-2, and not [3H]CP-55,940, indicating that the expressed CBRs exhibit atypical binding properties. Furthermore, [3H]WIN-55,212-2 bound to a single site in all cancer cells with high affinity and varying densities. CBR characteristics were next compared between human prostate cancer cell lines expressing low (PC-3) and high (DU-145) CBR density. Although mRNA for canonical CBRs was detected in both cell lines, only 5 out of 15 compounds with known high affinity for canonical CBRs displaced [3H]WIN-55,212-2 binding. Functional assays further established that CBRs in prostate cancer cells exhibit distinct signaling properties relative to canonical Gi/Go-coupled CBRs. Prostate cancer cells chronically exposed to both CBR agonists and antagonists/inverse agonists produced receptor downregulation, inconsistent with actions at canonical CBRs. Treatment of DU-145 cells with CBR ligands increased LDH-release, decreased ATP-dependent cell viability, and produced mitochondrial membrane potential depolarization. In summary, several cancer cell lines express CBRs with binding and signaling profiles dissimilar to canonical CBRs. Drugs selectively targeting these atypical CBRs might exhibit improved anti-cancer properties.

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Cannabinoid WIN 55,212-2 Inhibits Human Glioma Cell Growth by Triggering ROS-Mediated Signal Pathways

Cited by 8 publications

References 36 publications

LCS-1 inhibition of superoxide dismutase 1 induces ROS-dependent death of glioma cells and degradates PARP and BRCA1

LCS-1 inhibition of superoxide dismutase 1 induces ROS-dependent death of glioma cells and degradates PARP and BRCA1

Endocannabinoid signaling in glioma

Non-Canonical Cannabinoid Receptors with Distinct Binding and Signaling Properties in Prostate and Other Cancer Cell Types Mediate Cell Death

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