Molecular Mechanism of Autophagy and Its Regulation by Cannabinoids in Cancer

Lee, Xin Chien; Werner, Evelyn; Falasca, Marco

doi:10.3390/cancers13061211

Cited by 25 publications

(13 citation statements)

References 200 publications

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“…Oseltamivir also exerted differential effects on these liver Evidence has demonstrated dual roles of autophagy, namely, both tumor inhibitory and tumor promoting roles, in cancers. A variety of studies have revealed that autophagy promotes cancer cell death in early phases and survival in later phases (18)(19)(20). Autophagy may provide energy for excessive cancer cell proliferation or lead to the insufficient availability of nutrients for cancer cells by disrupting energy homeostasis, thus causing cell death (21).…”

Section: Discussionmentioning

confidence: 99%

Potential of antiviral drug oseltamivir for the treatment of liver cancer

et al. 2021

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Liver cancer is a leading cause of cancer-related mortality globally. Since hepatitis virus infections have been strongly associated with the incidence of liver cancer, studies concerning the effects of antiviral drugs on liver cancer have attracted great attention in recent years. The present study investigated the effects of two anti-hepatitis virus drugs, lamivudine and ribavirin, and one anti-influenza virus drug, oseltamivir, on liver cancer cells to assess alternative methods for treating liver cancer. MTT assays, wound healing assays, Τranswell assays, flow cytometry, immunoblotting, ELISA, immunofluorescence staining and a xenograft animal model were adopted to verify the effects of lamivudine, ribavirin and oseltamivir on liver cancer cells. Treatment with ribavirin and oseltamivir for 24 and 48 h significantly decreased the viability of both Huh-7 and HepG2 cells compared with that of THLE-3 cells in a dose-dependent manner. The subsequent investigations focused on oseltamivir, considering the more serious clinical adverse effects of ribavirin than those of oseltamivir. Significantly decreased migration and invasion were observed in both Huh-7 and HepG2 cells that were treated with oseltamivir for 24 and 48 h. In addition, oseltamivir significantly increased autophagy in Huh-7 cells, as revealed by the significantly higher ratios of LC3-II/LC3-I, increased expression of Beclin-1, and decreased expression of p62, whereas no significant increases in the expression of apoptosis-related proteins, including Apaf-1, cleaved caspase-3, and cleaved PARP-1, were detected. Notably, apoptosis and autophagy were significantly increased in HepG2 cells in the presence of oseltamivir, as revealed by the significant increases in the expression of Apaf-1, cleaved caspase-3, and cleaved PARP-1, the higher ratios of LC3-II/LC3-I, the increased expression of Beclin-1, and the decreased expression of p62. Additionally, significant inhibitory effects of oseltamivir on xenografted Huh-7 cells in athymic nude mice were observed. The present study, for the first time to the best of our knowledge, reported the differential effects of oseltamivir on inducing liver cancer cell death both in vitro and in vivo and may provide an alternative approach for treating liver cancer.

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Section: Discussionmentioning

confidence: 99%

Potential of antiviral drug oseltamivir for the treatment of liver cancer

et al. 2021

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“…We observed that CBD homologs induced changes in ROS levels and cellular processes related to ROS signaling. Furthermore, CBD homologs affected the morphology and functionality of several cell structures, such as mitochondria and ER, as already demonstrated for natural CBD [ 21 ]. The combination of CBD homologs with drugs that inhibit the activity of enzymes involved in the metabolism of endocannabinoids, such as the monoacylglycerol lipase (MAGL), or with drugs that induce the activation of cellular stress pathways, such as the phorbol ester 12-myristate 13-acetate (PMA), is associated with an extensive vacuolization, hyper-increased ROS levels, and multiple alterations in organelles structure.…”

Section: Introductionmentioning

confidence: 69%

Oxidative Stress and Multi-Organel Damage Induced by Two Novel Phytocannabinoids, CBDB and CBDP, in Breast Cancer Cells

et al. 2021

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Over the last few years, much attention has been paid to phytocannabinoids derived from Cannabis for their therapeutic potential. Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) are the most abundant compounds of the Cannabis sativa L. plant. Recently, novel phytocannabinoids, such as cannabidibutol (CBDB) and cannabidiphorol (CBDP), have been discovered. These new molecules exhibit the same terpenophenolic core of CBD and differ only for the length of the alkyl side chain. Roles of CBD homologs in physiological and pathological processes are emerging but the exact molecular mechanisms remain to be fully elucidated. Here, we investigated the biological effects of the newly discovered CBDB or CBDP, compared to the well-known natural and synthetic CBD (nat CBD and syn CBD) in human breast carcinoma cells that express CB receptors. In detail, our data demonstrated that the treatment of cells with the novel phytocannabinoids affects cell viability, increases the production of reactive oxygen species (ROS) and activates cellular pathways related to ROS signaling, as already demonstrated for natural CBD. Moreover, we observed that the biological activity is significantly increased upon combining CBD homologs with drugs that inhibit the activity of enzymes involved in the metabolism of endocannabinoids, such as the monoacylglycerol lipase (MAGL) inhibitor, or with drugs that induces the activation of cellular stress pathways, such as the phorbol ester 12-myristate 13-acetate (PMA).

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“…While several blood and urine biomarkers and imaging techniques have been developed to predict PCa ( 25 , 26 ), as far as we know no biomarker is available for the diagnosis of prostate inflammation. At a time when immunotherapy is taking hold, the identification of cases with prostatic inflammation is of considerable interest for targeted immunological therapies ( 27 ).…”

Section: Discussionmentioning

confidence: 99%

PSA Density Help to Identify Patients With Elevated PSA Due to Prostate Cancer Rather Than Intraprostatic Inflammation: A Prospective Single Center Study

et al. 2021

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The association between PSA density, prostate cancer (PCa) and BPH is well established. The aim of the present study was to establish whether PSA density can be used as a reliable parameter to predict csPCa and to determine its optimal cutoff to exclude increased PSA levels due to intraprostatic inflammation. This is a large prospective single-center, observational study evaluating the role of PSA density in the discrimination between intraprostatic inflammation and clinically significant PCa (csPCa). Patients with PSA ≥ 4 ng/ml and/or positive digito-rectal examination (DRE) and scheduled for prostate biopsy were enrolled. Prostatic inflammation (PI) was assessed and graded using the Irani Scores. Multivariable binary logistic regression analysis was used to assess if PSA density was associated with clinically significant PCa (csPCa) rather than prostatic inflammation. A total of 1988 patients met the inclusion criteria. Any PCa and csPCa rates were 47% and 24% respectively. In the group without csPCa, patients with prostatic inflammation had a higher PSA (6.0 vs 5.0 ng/ml; p=0.0003), higher prostate volume (58 vs 52 cc; p<0.0001), were more likely to have a previous negative biopsy (29% vs 21%; p=0.0005) and a negative DRE (70% vs 65%; p=0.023) but no difference in PSA density (0.1 vs 0.11; p=0.2). Conversely in the group with csPCa, patients with prostatic inflammation had a higher prostate volume (43 vs 40 cc; p=0.007) but no difference in the other clinical parameters. At multivariable analysis adjusting for age, biopsy history, DRE and prostate volume, PSA density emerged as a strong predictor of csPCA but was not associated with prostatic inflammation. The optimal cutoffs of PSA density to diagnose csPCa and rule out the presence of prostatic inflammation in patients with an elevated PSA (>4 ng/ml) were 0.10 ng/ml2 in biopsy naïve patients and 0.15 ng/ml2 in patients with a previous negative biopsy. PSA density rather than PSA, should be used to evaluate patients at risk of prostate cancer who may need additional testing or prostate biopsy. This readily available parameter can potentially identify men who do not have PCa but have an elevated PSA secondary to benign conditions.

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Molecular Mechanism of Autophagy and Its Regulation by Cannabinoids in Cancer

Cited by 25 publications

References 200 publications

Potential of antiviral drug oseltamivir for the treatment of liver cancer

Potential of antiviral drug oseltamivir for the treatment of liver cancer

Oxidative Stress and Multi-Organel Damage Induced by Two Novel Phytocannabinoids, CBDB and CBDP, in Breast Cancer Cells

PSA Density Help to Identify Patients With Elevated PSA Due to Prostate Cancer Rather Than Intraprostatic Inflammation: A Prospective Single Center Study

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