Allicin regulates Sestrin2 ubiquitination to affect macrophage autophagy and senescence, thus inhibiting the growth of hepatoma cells.

BACKGROUND: Allicin regulates macrophage autophagy and senescence, and inhibits hepatoma cell growth. This study investigated the mechanism by which allicin inhibits the growth of hepatoma cells. METHODS: Hepa1-6 mouse hepatoma cells were subcutaneously injected into C57BL/6 J mice to construct a tumor transplantation model. Macrophages were cultured with the supernatant of hepatoma cells to construct a cell model. The levels of mRNA and proteins and the level of Sestrin2 ubiquitination were measured by RTqPCR, immunofluorescence and Western blotting. The levels of autophagy-related factors and the activity of senescence-associated ß-galactosidase were determined by kits, and protein stability was detected by cycloheximide (CHX) tracking. RESULTS: Data analysis of clinical samples revealed that RBX1 was highly expressed in tumor tissues, while Sestrin2 was expressed at low levels in tumor tissues. Allicin can promote the expression of the autophagy-related proteins LC3 and Beclin-1 in tumor macrophages and inhibit the expression of the aging-related proteins p16 and p21, thus promoting autophagy in macrophages and inhibiting cell senescence. Moreover, allicin can inhibit the expression of RBX1, thereby reducing the ubiquitination of Sestrin2, enhancing the stability of Sestrin2, activating autophagy in tumor macrophages and inhibiting senescence. In addition, allicin treatment inhibited the proliferation and migration of hepatoma carcinoma cells cocultured with macrophages and significantly improved the development of liver cancer in mice. CONCLUSION: Allicin can affect the autophagy of macrophages and restrain the growth of hepatoma cells by regulating the ubiquitination of Sestrin2.

Intraoperative radiotherapy in breast cancer: Alterations to the tumor microenvironment and subsequent biological outcomes (Review).

Intraoperative radiotherapy (IORT) is a precise, single high­dose irradiation directly targeting the tumor bed during surgery. In comparison with traditional external beam RT, it minimizes damage to other normal tissues, ensures an adequate dose to the tumor bed and results in improved cosmetic outcomes and quality of life. Furthermore, IORT offers a shorter treatment duration, lower economic costs and therapeutic efficacy comparable with traditional RT. However, its relatively higher local recurrence rate limits its further clinical applications. Identifying effective radiosensitizing drugs and rational RT protocols will improve its advantages. Furthermore, IORT may not only damage DNA to directly kill breast tumor cells but also alter the tumor microenvironment (TME) to exert a sustained antitumor effect. Specific doses of IORT may exert anti­angiogenic effects, and consequently antitumor effects, by impacting post­radiation peripheral blood levels of vascular endothelial growth factor and delta­like 4. IORT may also modify the postoperative wound fluid composition to continuously inhibit tumor growth, e.g. by reducing components such as microRNA (miR)­21, miR­221, miR­115, oncostatin M, TNF­ß, IL­6 and IL­8, and by elevating levels of components such as miR­223, to inhibit the ability of postoperative wound fluid to induce proliferation, invasion and migration of residual cancer cells. IORT can also modify cancer cell glucose metabolism to inhibit the proliferation of residual tumor cells. In addition, IORT can induce a bystander effect, eliminating the postoperative wound fluid­induced epithelial­mesenchymal transition and tumor stem cell phenotype. Insights gained at the molecular level may provide new directions for identifying novel therapeutic targets and approaches. A more comprehensive understanding of the effects of IORT on the breast cancer (BC) TME may further its clinical application. Hence, the present article reviews the primary effects of IORT on BC and its impact on the TME, aiming to offer fresh research perspectives for relevant professionals.

Dentatin exerts anticancer effects on human colon cancer cell lines via cell cycle arrest, autophagy, inhibition of cell migration and JAK/STAT signalling pathway.

PURPOSE: Colon cancer is a malignant disease with significant mortality. In the present study the anticancer effects of a carbazole alkaloid, Dentatin, were examined against colon cancer cells. METHODS: The colon cancer HT-29 cell line and the normal CCD-18 CO colon cell line were used in the present study. MTT assay was used to check the proliferation rate of the cancer cells. Autophagy was detected by electron microscopy. DNA damage was checked by alkaline comet assay. Cell cycle analysis was performed by flow cytometry. Cell migration was monitored by wound healing assay. Protein expression was checked by western blot analysis. RESULTS: The results showed that Dentatin inhibited the growth of HT-29 cancer cells in a concentration-dependent manner and with IC50 of 25 µM. However, the IC50 of Dentatin against the normal CCD-18CO colon cells was four times higher (ie.,100 µM). Dentatin inhibited the proliferation of the HT-29 cancer cells by triggering S-phase arrest. This was also accompanied with increase in the expression of cyclin D1 and decrease in the expression of Cyclin A and B1. Moreover, Dentatin also induced autophagy in the HT-29 cells which was associated with upregulation of LC3 II and downregulation of Beclin-1 expression. Comet assay revealed that Dentatin induced DNA damage in the HT-29 cells. Dentatin also significantly inhibited the migration of the HT-29 cells. Finally the effects of Dentatin were examined on the JAK/STAT signalling pathway and it was found that Dentatin inhibited this pathway. CONCLUSION: Dentatin may prove to be an essential lead molecule for the management of colon cancer.

UGT1A1*6 polymorphisms are correlated with irinotecan-induced neutropenia: a systematic review and meta-analysis.

Irinotecan (IRI) chemotherapy toxicities can be severe, and may result in treatment delay, morbidity and in some rare cases death. Neutropenia is a life-threatening side effect of irinotecan, and UDP glucuronosyltransferases (UGTs) gene polymorphisms could predict the side effects in cancer patients and then reduce IRI-induced toxicity by preventative treatment or a decrease in dose. Both UGT1A1*6 and *28 were reliably demonstrated to be risk factors for IRI-induced neutropenia, with tests for both polymorphisms potentially being particularly useful in Asian cancer patients. However, some researchers reported that UGT1A1*6 could predict IRI-induced toxicities in Asian populations, controversial conclusions still remained. Thus, the association between UGT1A1*6 polymorphisms and IRI-induced severe toxicity in cancer patients is still needed to be explored. Therefore, this study aims to investigate the association between UGT1A1*6 polymorphisms and IRI-related severe neutropenia in cancer patients on a large scale. A total of 12 studies that included 746 wild genotype (G/G) cases and 394 variant genotype (G/A and A/A) cases were included on the basis of inclusion criteria. Then we assessed the methodologies quality; odds ratio (OR), risk difference (RD) and 95% confidence intervals (95% CI) were used to assess the strength of association. Overall, an increased risk of severe neutropenia in cancer patients with UGT1A1*6 polymorphisms was found. Patients with recessive models (GA + AA vs. GG) of UGT1A1*6 showed an increased risk (OR 2.03, 95% CI 1.54-2.68; RD = 0.11, P < 0.001). Specifically, the heterozygous variant of UGT1A1*6 showed an increased risk (OR 1.83, 95% CI 1.36-2.46; RD = 0.09, P < 0.001), and homozygous mutation showed also high risk (OR 2.95, 95% CI 1.83-4.75; RD = 0.18, P < 0.001) for severe neutropenia. Subgroup meta-analysis revealed that for patients harboring both heterozygous and homozygous variants, cancer types, low dose of IRI and the duration of treatment also presented comparably increased risk in suffering severe neutropenia. As for country, in China and Japan, there was a statistically increased severe neutropenia with variant genotype of UGT1A1*6 (China: GA + AA vs. GG, OR 1.83, 95% CI 1.28-2.59; RD = 0.08, P = 0.001; Japan: GA + AA vs. GG, OR 2.39, 95% CI 1.45-3.92; RD = 0.15, P = 0.001). In conclusion, in this meta-analysis, the UGT1A1*6 polymorphisms were associated with an increased risk of IRI-induced neutropenia in cancer patients, and increased incidences of severe neutropenia could be correlated with diverse regions, cancer type, low dose of IRI and the duration of treatment.

A novel transdermal patch incorporating isosorbide dinitrate with bisoprolol: in vitro and in vivo characterization.

The combination therapy of nitrate and selective beta-adrenoceptor antagonist has shown benefits for treatment of hypertension and heart disease than either drug alone. The objectives of the present study were to define effects on the anti-hypertension activity and pharmacokinetics of a novel transdermal patch incorporating isosorbide dinitrate (ISDN) with bisoprolol (BP). The 3:2 ratio of ISDN to BP (mg/mg) in the transdermal patches exhibited better anti-hypertension effect synergistically with a similar inhibiting heart rates effect to that of BP alone in renovascular hypertensive rats, and was therefore selected as a final formulation. The in vitro transdermal penetration of both ISDN and BP from the patches displayed a zero-order process, and the penetration rate constants were 7.4 microg/(cm(2)h) for ISDN, and 5.9 microg/(cm(2)h) for BP, respectively. After transdermal administration at single dose or multiple doses, the synergistic anti-hypertension effect was confirmed in spontaneously hypertensive rats also. The effect of each patch lasts for 3 days, and increased with the total dose of two drugs (2mg/cm(2), ISDN:BP=3:2, mg/mg), showing a dose dependant manner. After transdermal administration to rabbits, the absolute bioavailabilities were 33.6% for ISDN, and 31.3% for BP, respectively. The maximal concentrations (C(max)) of both drugs were significantly reduced while the areas under the plasma concentration-time curve (AUC), and mean residence times (MRT) were evidently increased and extended, respectively. As a patient-friendly, convenient, and multi-day dosing therapeutic system, the transdermal patches incorporating ISDN and BP could be promising for prevention and treatment of hypertension.