Cell
MinireviewApoptosis in cancer therapy: Crossing the threshold
References (30)
- G.I. Evan et al.
Cell
(1992) - L. Hartwell
Cell
(1992) - D.M. Hockenbery et al.
Cell
(1993) - S.J. Korsmeyer
Immunol. Today
(1992) - L.R. Livingstone et al.
Cell
(1992) - S.W. Lowe et al.
Cell
(1993) - B. Vogelstein et al.
Cell
(1992) - Y. Yin et al.
Cell
(1992) - D.S. Askew et al.
Oncogene
(1991) - N. Bardeesy et al.
Nature Genet.
(1994)
Nature
Nature
br. J. Cancer
Cancer Cells
Cited by (1396)
QSOX2 Upregulated in triple-negative breast cancer exacerbates patient prognosis by stabilizing integrin β1
2024, HeliyonBreast cancer (BC) remains a significant global health threat, with triple-negative breast cancer (TNBC) standing out as a particularly aggressive subtype lacking targeted therapies. Addressing this gap, we propose Quiescin Q6 sulfhydryl oxidase 2 (QSOX2) as a potential therapeutic target, a disulfide bond-forming enzyme implicated in cancer progression. Using publicly available datasets, we conducted a comprehensive analysis of QSOX2 expression in BC tumor and non-tumor tissues, assessing its specificity across different molecular subtypes. We further explored correlations between QSOX2 expression and patient outcomes, utilizing datasets like TCGA and METABRIC. In addition, we performed in vitro experiments to evaluate QSOX2 expression in BC cell lines and investigate the effects of QSOX2 knockdown on various TNBC cellular processes, including cell proliferation, apoptosis resistance, migration, and the epithelial-to-mesenchymal transition (EMT). Our results reveal significantly elevated QSOX2 expression in BC tumor tissues, particularly in TNBC, and establish an association between high QSOX2 expression and increased patient mortality, cancer progression, and recurrence across various BC subtypes. Notably, QSOX2 knockdown in TNBC cell lines reduces cell proliferation, enhances apoptosis, and suppresses migration, potentially mediated through its influence on the EMT process. Furthermore, we identify a significant link between QSOX2 and integrin β1 (ITGB1), suggesting that QSOX2 enhances ITGB1 stability, subsequently exacerbating the malignancy of TNBC. In conclusion, elevated QSOX2 expression emerges as a key factor associated with adverse patient outcomes in BC, particularly in TNBC, contributing to disease progression through various mechanisms, including the modulation of ITGB1 stability. Our findings underscore the potential of targeting QSOX2 as a therapeutic strategy for improving patient prognoses not only in TNBC but also in other BC subtypes.
Design, synthesis, biological evaluation and molecular docking study of new pyrazolo[1,5-a]pyrimidines as PIM kinase inhibitors and apoptosis inducers
2024, Journal of Molecular StructureThis study involved designing and synthesizing new derivatives of pyrazolo[1,5-a]pyrimidine 5a-l, which were prepared via reaction of 4-Arylazo-1H-pyrazole-3,5-diamines 3a,b with arylidenemalononitriles (4a-f) in refluxing methanol. The structure of the synthesized derivatives were confirmed using different spectroscopic techniques. Virtual screening was achieved for the newly designed derivatives using docking simulation between the target pyrazolo[1,5-a]pyrimidine 5j and the active binding site of the PIM-1 enzyme. The cytotoxicity of novel derivatives of pyrazolo[1,5-a]pyrimidine framework was screened on the cancer cell lines: colon (HCT-116), hepatocellular (Hep-G2), and breast (MCF-7). Comparing with doxorubicin, compounds 2,5-diamino-7-(4-ethoxyphenyl)-3-(p-tolyldiazenyl)pyrazolo[1,5-a]pyrimidine-6-carbonitrile; 5h, 2,5-diamino-7-(4-hydroxy-3-methoxyphenyl)-3-(p-tolyldiazenyl)pyrazolo[1,5-a]pyrimidine-6-carbonitrile; 5j, and 2,5-diamino-7-(furan-2-yl)-3-(p-tolyldiazenyl)pyrazolo[1,5-a]pyrimidine-6-carbonitrile; 5l exhibited noteworthy anticancer properties, with half maximal inhibitory concentration (IC50 range) = 1.26–3.22 μM. In addition, the most potent compound, 5j demonstrated a lower level of toxicity towards normal cells (WI-38 cell line), suggesting an increased level of safety. Compounds 5h, 5j, and 5l were evaluated for their activity against three different PIM kinases (PIM-1, PIM-2, and PIM-3 enzymes) in an effort to elucidate their inhibitory potential on PIM kinases. Additionally, the apoptotic potency of 5j was assessed on MCF-7 cells. Results revealed that compound 5j was potent against both PIM-1 and PIM-2 having IC50 0.158 and 0.297 μM, respectively, comparing to staurosporine's IC50 0.294 and 0.477 μM against both enzymes, respectively, while its inhibitory activity against PIM-3 enzyme was moderate. In addition, compound 5j promoted apoptosis via elevating the levels of Bax, p53, and caspase-3 and dropping down Bcl-2 level. G1 phase arrest of cell cycle was also observed. Furthermore, docking analyses of 5j in the PIM-1 binding site was conducted.
Correlation of Bcl-2 expression with prognosis and survival in patients with head and neck cancer: A systematic review and meta-analysis
2023, Critical Reviews in Oncology/HematologyHead and neck cancer (HNC) is a growing disease, affecting more than 700.000 cases per year and ranking as the sixth most prevalent type of cancer worldwide. The impossibility of properly entering into apoptosis directly influences uncontrolled growth and consequently tumor development and progression. Bcl-2 emerged as a key regulator in the balance between cell apoptosis and proliferation in apoptosis machinery. This systematic review and meta-analysis aimed to review all published studies investigating changes in Bcl-2 protein expression assessed by immunohistochemistry (IHC) and related to prognostic and survival values of patients with HNC. After applying the inclusion and exclusion factors, we reached the number of 20 articles included in the meta-analysis. The random-effect pooled HR (CI95%) value of OS related to Bcl-2 IHC expression in tissues from HNC patients was 1.80 (CI95% 1.21–2.67) (p 0.0001) and DFS was 1.90 (CI95% 1.26–2.86 (p 0.0001). The OS value for the specific oral cavity tumors was 1.89 (1.34–2.67), while in the larynx it was 1.77 (0.62–5.06), and the DFS in the pharynx was 2.02 (1.46–2.79). The univariate and multivariate analyses of OS were respectively 1.43 (1.11–1.86) and 1.88 (1.12–3.16), while in DFS it was 1.70 (0.95–3.03) and 2.08 (1.55–2.80). The OS considering a low cut-off for Bcl-2 positivity was 1.19 (0.60–2.37) and DFS was 1.48 (0.91–2.41), while studies with a high cut-off demonstrated OS of 2.28 (1.47–3.52) and DFS of 2.77 (1.74–4.40). Our meta-analysis demonstrates that Bcl-2 protein overexpression can result in worse LNM, OS, and DFS in patients with HNC, however, it is not a reliable conclusion, due to the wide divergences between the original studies and the fact that many studies have a very high range of confidence and also a high risk of bias.
The mycelium of the Trametes versicolor synn. Coriolus versicolor (Turkey tail mushroom) exhibit anti-melanoma activity in vitro
2023, Biomedicine and PharmacotherapyMelanoma is one of the most aggressive forms of skin cancer and is characterized by high metastatic potential. Despite improvements in early diagnosis and treatment, the mortality rate among metastatic melanoma patients continues to represent a significant clinical challenge. Therefore, it is imperative that we search for new forms of treatment. Trametes versicolor is a mushroom commonly used in Chinese traditional medicine due to its numerous beneficial properties. In the present work, we demonstrate T. versicolor fruiting body and mycelium ethanol extracts exhibit potent cytotoxic activity towards A375 (IC50 = 663.3 and 114.5 µg/mL respectively) and SK-MEL-5 (IC50 = 358.4 and 88.6 µg/mL respectively) human melanoma cell lines. Further studies revealed that T. versicolor mycelium extract induced apoptotic cell death and poly (ADP-ribose) polymerase cleavage, upregulated the expression of autophagy-associated marker LC3-II, increased the presentation of major histocompatibility complex II and expression of programmed death-ligand receptor, and inhibited cell migration in SK-MEL-5 cells. Therefore, our present findings highlight the therapeutic potential of T. versicolor mycelium extract for the treatment of melanoma and merit further study.
Nisin delivery by nanosponges increases its anticancer activity against in-vivo melanoma model
2023, Journal of Drug Delivery Science and TechnologyNisin, a small antimicrobial peptide, has been recently suggested as a novel potential therapeutic approach to treat cancer with no toxicity in humans. The current study used cross-linked-cyclodextrin nanosponges (CDNS) to load Nisin-Z to study the complexes' capacity against melanoma cancer in vitro and in vivo. In-vitro results showed that Nisin encapsulated in both CDNSs (PMDA and CDI-NSs) behaves as an effective antitumor agent by increasing the cytotoxicity and apoptosis against melanoma cancer cell lines (B16-F10). Furthermore, Nisin loaded on PMDA-NSs significantly inhibited the in-vivo growth of melanoma cancer in a mouse model compared to free Nisin-Z. Indeed, the weight and volume of melanoma tumors were outstandingly decreased in the group treated with Nisin-PMDA-NSs compared to free Nisin. On the other hand, the anti-cancer effects of Nisin related to its apoptosis and antioxidant activity were remarkably increased in complex with PMDA-NSs. Moreover, Nisin in nano-formulation led to a considerable decrease of CD31, an angiogenesis factor, expression in tumor tissues. Our findings suggest that incorporating Nisin into nanosponges as a safe carrier may improve Nisin's antitumor effect in melanoma cancer animal models.
Curcuma aeruginosa Roxb. exhibits cytotoxicity in A-549 and HeLa cells by inducing apoptosis through caspase-dependent pathways
2022, Biomedicine and PharmacotherapyThe aim of the current study was to examine the efficacy of the leaf, stem and rhizome of Curcuma aeruginosa Roxb. for their phytochemical content, antioxidant and anti-cancer activities. The different parts of C. aeruginosa were subjected to sequential extraction to give three fractions viz., hexane, ethyl acetate and methanol extract. The cytotoxic effect and the mode of action against A-549 human lung adenocarcinoma and HeLa cell lines were examined. C. aeruginosa presented no significant toxic effect in normal human lung cells (L-132). The methanol extracts were found to be the most cytotoxic and further investigation was carried out to understand the effects. The methanol extracts induced DNA damage after 24 h with significant increase in tail DNA and tail moment when compared to untreated control. Up-regulation in the expression of the caspase − 8 and − 3 activity was observed after 48 h of treatment. The mechanism of cell death and apoptosis induced by the methanol extracts on A549 and HeLa cells were studied using fluorescent staining. Bioactive compounds detected from the HPLC revealed phenol and flavonoid compounds: Gallic acid, quercetin, caffeic acid, kaempferol, rutin, coumaric acid and naringenin. GC-MS results identified the presence of sesquiterpenoids: α-curcumene, curzerene curcumenol, curzerenone epicurzerenone, caryophyllene oxide and diterpenoid, andrographolide. These compounds are known for inducing apoptosis in human cancer cells through caspase - dependent pathways. Therefore, C. aeruginosa and its potential to induce apoptosis in cancer cells suggest that they have potential in medical applications.