The purpose of this paper is to evaluate the pharmacodynamics of a new 5-HT2A receptor inverse agonist PCC03039 and provide data support for its druggability and clinical trial application. In the in vitro efficacy studies, the affinities of PCC03039 for 5-HT2A, 5-HT2B, and 5-HT2C receptors and the inverse agonistic and antagonistic activities of 5-HT2A receptors were detected; in the in vivo efficacy studies, the pharmacodynamic effects of PCC03039 on DOI-induced rat head-twitch model and MK-801-induced rat hyperlocomotion model were observed. The results of the studies showed that the affinities of PCC03039 for the 5-HT2 receptors were comparable to those of the marketed drug pimavanserin, however, the inverse agonistic and antagonistic activities of PCC03039 for the 5-HT2A receptor were significantly improved, with IC50 values of 2.11 nM and 1.33 nM, which were 20-fold and 21-fold higher than that of pimavanserin, respectively. PCC03039 could dose-dependently inhibit DOI-induced head-twitch and MK-801-induced hyperlocomotion in SD rats, and the pharmacodynamic effect was significantly better than pimavanserin at the equimolar dose. The above results show that PCC03039 has better pharmacodynamic activity in vitro and in vivo than pimavanserin, and has good druggability from the perspective of pharmacodynamics.
Activation of DNA damage repair pathways in tumor cells may reduce the treatment efficacy of platinum-based chemotherapeutic agents. Ubiquitin-specific protease 7 (USP7) is one of the deubiquitinating enzymes that can remove the ubiquitin from target proteins and protect substrate proteins from degradation. Although ubiquitin-specific protease 7(USP7) is highly expressed in cervical cancer tissues and plays an important role in DNA damage repair, the role of USP7 inhibition in the antitumor efficacy of cisplatin remains unknown. This study explored the effects and mechanisms of a USP7 inhibitor P22077 on the anti-cervical cancer efficacy of cisplatin. In in vitro studies, P22077 and cisplatin both significantly reduced HeLa cell proliferation and colony formation, and the combination produced preferable effects. In in vivo xenograft tumor model, P22077 and cisplatin both demonstrated significant antitumor efficacy. The drug combination produced greater antitumor activity than the individual drug alone. Cisplatin evoked DNA damage repair-related molecules and P22077 tended to prevent this change. The drug combination produced higher cell death rate than the individual drug alone. Collectively, These results suggest that the USP7 inhibitor P22077 alone has significant antitumor efficacy and also can enhance the antitumor effects of cisplatin. The USP7 inhibitor P22077 combined with cisplatin may be an effective treatment strategy for cervical cancer.
In vitro and in vivo evaluation of genotoxicity, cytotoxicity, and protective effects of synthetic chalcones (E)-3-(4-chlorophenyl)-1-phenyl-2-propen-1-one (4-CL) and (E)-3-(3,4-dimethoxyphenyl)-1- phenyl-2-propen-1-one (DMF)
The chalcones (E)-3-(4-chlorophenyl)-1-phenyl-2-propen-1-one (4-CL) and (E)-3-(3,4-dimethoxyphenyl)-1-phenyl-2 -propen-1-one (DMF) are versatile and easily synthesized into low-cost compounds that have a wide spectrum of biological activities. In this study, the cytotoxic, genotoxic and modulatory activities of 4-CL and DMF were evaluated using the Ames test and the mouse micronucleus assay. The results of the Ames test revealed that both chalcones did not show mutagenic activity in Salmonella typhimurium strains TA98 and TA100, and demonstrated significant antimutagenicity (p< 0.05) when co-administered with sodium azide (SA) in strain TA100. In the micronucleus assay, both showed a significant increase in the frequency of micronucleated polychromatic erythrocytes (MNPCE) at 24 h and 48 h, revealing a genotoxic effect. In the co-treatment with mitomycin C (MMC) there was a significant decrease (p< 0.05) in the frequency of MNPCE both in chalcones at 24h and in the less concentrated dose of DMF at 48h, demonstrating its antigenotoxic activity. 4-CL showed a significant decrease in the polychromatic/ normochromatic erythrocyte (PCE/ NCE) ratio at 24 and 48 h (p< 0.05), indicating cytotoxicity. However, 4-CL and DMF when co-administered with MMC showed a significant increase in the PCE/NCE ratio within 24 hours, demonstrating anticytotoxicity. Furthermore, a biphasic dose-response behavior was observed in both chalcones, 4-CL in the co-administration with SA, in the Ames Test and DMF in the co-treatment with MMC, at 48 hours of exposure, in the micronucleus assay. In this study, 4-CL and DMF showed genotoxic, cytotoxic, antigenotoxic, anticytotoxic and no mutagenic properties.