Inhibition of the cyclin‐dependent kinase (CDK) 4/6‐retinoblastoma (RB) pathway is an effective therapeutic strategy against cancer. Here, we performed a preclinical investigation of the antitumor activity of SHR6390, a novel CDK4/6 inhibitor. SHR6390 exhibited potent antiproliferative activity against a wide range of human RB‐positive tumor cells in vitro, and exclusively induced G 1 arrest as well as cellular senescence, with a concomitant reduction in the levels of Ser780‐phosphorylated RB protein. Compared with the well‐known CDK4/6 inhibitor palbociclib, orally administered SHR6390 led to equivalent or improved tumor efficacy against a panel of carcinoma xenografts, and produced marked tumor regression in some models, in association with sustained target inhibition in tumor tissues. Furthermore, SHR6390 overcame resistance to endocrine therapy and HER2‐targeting antibody in ER‐positive and HER2‐positive breast cancer, respectively. Moreover, SHR6390 combined with endocrine therapy exerted remarkable synergistic antitumor activity in ER‐positive breast cancer. Taken together, our findings indicate that SHR6390 is a novel CDK4/6 inhibitor with favorable pharmaceutical properties for use as an anticancer agent.
Cancer stem cells (CSCs), also known as tumor-initiating cells, are highly metastatic, chemo-resistant and tumorigenic, and are critical for cancer development, maintenance and recurrence. Oncolytic adenovirus could targetedly kill CSCs and has been acted as a promising anticancer agent. Currently, a novel GP73-regulated oncolytic adenovirus GD55 was constructed to specifically treat liver cancer and exhibited obvious cytotoxicity effect. However, there remains to be confirmed that whether GD55 could effectively eliminate liver CSCs. We first utilized the suspension culture to enrich the liver CSCs-like cells, which acquires the properties of liver CSCs in self-renewal, differentiation, quiescence, chemo-resistance and tumorigenicity. The results indicated that GD55 elicited more significant cytotoxicity and stronger oncolytic effect in liver CSC-like cells compared to common oncolytic virus ZD55. Additionally, GD55 possessed the greater efficacy in suppressing the growth of implanted tumors derived from liver CSC-like cells than ZD55. Furthermore, GD55 induced remarkable apoptosis of liver CSC-like cells in vitro and in vivo, and inhibited the propogation of cells and angiogenesis in xenograft tumor tissues. Thus, GD55 may virtually represent an attractive therapeutic agent for targeting liver CSCs to achieve better clinical outcomes for HCC patients.
An ongoing outbreak of severe respiratory illness and pneumonia caused by the severe acute respiratory coronavirus 2 (SARS-CoV-2) commenced in December 2019, and the disease was named as coronavirus disease 2019 (COVID-19). Soon after, scientists identified the characteristics of SARS-CoV-2, including its genome sequence and protein structure. The clinical manifestations of COVID-19 have now been established; and nucleic acid amplification is used for the direct determination of the virus, whereas immunoassays can determine the antibodies against SARS-CoV-2. Clinical trials of several antiviral drugs are ongoing. However, there is still no specific drugs to treat COVID-19. Traditional Chinese medicine (TCM) was used in the treatment of COVID-19 during the early stages of the outbreak in China. Some ancient TCM prescriptions, which were efficacious in the treatment of severe acute respiratory syndrome (SARS) in 2002–03 and the influenza pandemic (H1N1) of 2009, have been improved by experienced TCM practitioners for the treatment of COVID-19 based on their clinical symptoms. These developed new prescriptions include Lianhua Qingwen capsules/granules, Jinhua Qinggan granules and XueBiJing injection, among others. In this review, we have summarized the presenting features of SARS-CoV-2, the clinical characteristics of COVID-19, and the progress in the treatment of COVID-19 using TCMs.
Aim:The tumor suppressor in lung cancer-1 (TSLC1) is a candidate tumor suppressor of lung cancer, and frequently inactivated in primary non-small cell lung cancer (NSCLC). In this study, we investigated the effects of TSLC1 mediated by a dual-regulated oncolytic adenovirus on lung cancer, and the mechanisms underlying the antitumor actions. Methods: The recombinant virus Ad·sp-E1A (∆24) -TSLC1 was constructed by inserting the TSLC1 gene into the dual-regulated Ad·sp-E1A (∆24) vector, which contained the survivin promoter and a 24 bp deletion within E1A. The antitumor effects of Ad·sp-E1A (∆24) -TSLC1 were evaluated in NCI-H460, A549, and H1299 lung cancer cell lines and the normal fibroblast cell line MRC-5, as well as in A549 xenograft model in nude mice. Cell viability was assessed using MTT assay. The expression of TSLC1 and activation of the caspase signaling pathway were detected by Western blot analyses. The tumor tissues from the xenograft models were examined using H&E staining, IHC, TUNEL, and TEM analyses. Results: Infection of A549 lung cancer cells with Ad·sp-E1A (∆24) -TSLC1 induced high level expression of TSLC1. Furthermore, the Ad·sp-E1A (∆24) -TSLC1 virus dose-dependently suppressed the viability of NCI-H460, A549, and H1299 lung cancer cells, and did not affect MRC-5 normal fibroblast cells. Infection of NCI-H460, A549, and H1299 lung cancer cells with Ad·sp-E1A (∆24) -TSLC1 induced apoptosis, and increased activation of caspase-8, caspase-3 and PARP. In A549 xenograft model in nude mice, intratumoral injection of Ad·sp-E1A (∆24) -TSLC1 significantly suppressed the tumor volume, and increased the survival rate (from less than 15% to 87.5% at d 60). Histological studies showed that injection of Ad·sp-E1A (∆24) -TSLC1 caused tumor cell apoptosis and virus particle propagation in tumor tissues. Conclusion: The oncolytic adenovirus Ad·sp-E1A (∆24) -TSLC1 exhibits specific antitumor effects, and is a promising agent for the treatment of lung cancer.
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