Chengying Xie

YN968D1 is a novel and selective inhibitor of vascular endothelial growth factor receptor-2 tyrosine kinase with potent activity in vitro and in vivo.

Angiogenesis is an important process in cell development, especially in cancer. Vascular endothelial growth factor (VEGF) signaling is an important regulator of angiogenesis. Several therapies that act against VEGF signal transduction have been developed, including YN968D1, which is a potent inhibitor of the VEGF signaling pathway. This study investigated the antitumor activity of YN968D1 (apatinib mesylate) in vitro and in vivo. YN968D1 potently suppressed the kinase activities of VEGFR‐2, c‐kit and c‐src, and inhibited cellular phosphorylation of VEGFR‐2, c‐kit and PDGFRβ. YN968D1 effectively inhibited proliferation, migration and tube formation of human umbilical vein endothelial cells induced by FBS, and blocked the budding of rat aortic ring. In vivo, YN968D1 alone and in combination with chemotherapeutic agents effectively inhibited the growth of several established human tumor xenograft models with little toxicity. A phase I study of YN968D1 has shown encouraging antitumor activity and a manageable toxicity profile. These findings suggest that YN968D1 has promise as an antitumor drug and might have clinical benefits. (Cancer Sci 2011; 102: 1374–1380)

Antitumor activity of lobaplatin alone or in combination with antitubulin agents in non-small-cell lung cancer.

ObjectiveLobaplatin is used to treat patients with breast cancer, small-cell lung cancer, and chronic myelogenous leukemia in China. In this study, we assessed the in-vitro and in-vivo activities of lobaplatin alone or in combination with antitubulin agents against human non-small-cell lung cancer (NSCLC). MethodsThe cytotoxicities of lobaplatin against NSCLC cells were determined by the sulforhodamine B (SRB) assay. Cell cycle analysis and apoptosis were assessed using flow cytometry, and the in-vivo antitumor activities were evaluated in human NSCLC xenografts in nude mice. ResultsThe cytotoxicity of lobaplatin was similar to or higher than that of cisplatin and carboplatin, with a mean IC50 of 2.5 &mgr;mol/l in a variety of NSCLC cells. In addition, lobaplatin arrested cells in the S phase and triggered apoptosis. The combination of lobaplatin with antitubulin agents yielded synergistic cytotoxic activity in vitro. In NSCLC xenografts, lobaplatin alone showed significant antitumor activity. The combination of lobaplatin with antitubulin agents, especially with paclitaxel, led to significantly enhanced activity, which was superior to that of cisplatin combined with antitubulin agents. ConclusionThese data demonstrate that the use of lobaplatin alone or in combination with antitubulin agents might be a rational and novel therapeutic strategy for human NSCLC and warrants further clinical investigation.

A novel water-soluble heptaplatin analogue with improved antitumor activity and reduced toxicity.

A novel water-soluble heptaplatin analogue, cis-[(4R,5R)-4,5-bis-(aminomethyl)-2-isopropyl-1,3-dioxolane](3-hydroxy-1,1-cyclobutanedicarboxylato)platinum(II), has been synthesized and biologically evaluated. The complex shows more activity and less toxicity than its parent drug heptaplatin, exhibiting the great potential for further development.

NL-103, a novel dual-targeted inhibitor of histone deacetylases and hedgehog pathway, effectively overcomes vismodegib resistance conferred by Smo mutations

Misregulation of hedgehog (Hh) signaling has been implicated in the pathogenesis of basal cell carcinoma (BCC) and medulloblastoma. Vismodegib, an orally bioavailable Hh signal pathway inhibitor targeting Smo, has been approved for the treatment of advanced BCC. However, acquired drug resistance to vismodegib induced by point mutation in Smo is emerging as a major problem to vismodegib treatment. In this study, we designed and synthesized a novel chimeric compound NL‐103, which comprises structural elements of Hh pathway inhibitor vismodegib, and histone deacetylase (HDAC) inhibitor vorinostat. NL‐103 simultaneously and significantly inhibited both HDACs and Hh pathway. Importantly, NL‐103, as well as vorinostat, effectively overcame vismodegib resistance induced by Smoothened point mutations. Moreover, NL‐103 and vorinostat, but not vismodegib, significantly downregulated the expression of Gli2 which plays an important role in Hh pathway. These results indicate that HDAC inhibitory activity is essential for NL‐103 to overcome vismodegib resistance and that dual inhibition of HDAC and Hh signaling pathway may be a rational strategy for overcoming vismodegib resistance. Our findings suggest that NL‐103 may be a promising compound for clinical development as a more effective Hh pathway inhibitor.

Synthesis, anticancer activity and toxicity of a water-soluble 4S,5S-derivative of heptaplatin, cis-{Pt(II)[(4S,5S)-4,5-bis(aminomethyl)-2-isopropyl-1,3-dioxolane]·(3-hydroxyl-cyclobutane-1,1-dicarboxylate)}.

A water-soluble 4S,5S-derivative of heptaplatin, cis-{Pt(II)[(4S,5S)-4,5-bis(aminomethyl)-2-isopropyl-1,3-dioxolane]·(3-hydroxyl-cyclobutane-1,1-dicarboxylate)} was synthesized. The anticancer activity and toxicity were evaluated by comparing its interaction with DNA, cytotoxicity against four human cancer cell lines, antitumor efficiency in human gastric carcinoma NCI-N87 xenografts in nude mice, and preliminary side-effects in rats to those of its 4R,5R-optical isomer which is under preclinical development. Both isomers induce condensation of DNA to the same extent and have similar cytotoxicity, but show different antitumor activity and toxicity, probably owing to the difference in respective pharmacokinetic profiles. 4S,5S-Isomer seems to exhibit superior antitumor activity and less toxicity than 4R,5R-optical isomer as well as the parent heptaplatin. These results imply that 4S,5S-configuration as a new drug candidate may be better than 4R,5R-counterpart.

Phosphodiesterase 3/4 Inhibitor Zardaverine Exhibits Potent and Selective Antitumor Activity against Hepatocellular Carcinoma Both In Vitro and In Vivo Independently of Phosphodiesterase Inhibition

Hepatocellular carcinoma (HCC) is the fifth common malignancy worldwide and the third leading cause of cancer-related death. Targeted therapies for HCC are being extensively developed with the limited success of sorafinib. In the present study, we investigated the potential antitumor activity of zardaverine, a dual-selective phosphodiesterase (PDE) 3/4 inhibitor in HCC cells both in vitro and in vivo. Although all zardaverine, PDE3 inhibitor trequinsin and PDE4 inhibitor rolipram increased intracellular cAMP levels through inhibiting PDE activity, only zardaverine significantly and selectively inhibited the proliferation of certain HCC cells, indicating that the antitumor activity of zardaverine is independent of PDE3/4 inhibition and intracellular cAMP levels. Further studies demonstrated that zardaverine induced G0/G1 phase cell cycle arrest of sensitive HCC cells through dysregulating cell cycle-associated proteins, including Cdk4, Cdk6, Cdk2, Cyclin A, Cyclin E, p21 and Rb. Notably, Rb expression was reversely related to the cell sensitivity to zardaverine. The present findings indicate that zardaverine may have potential as targeted therapies for some HCC, and the likely mechanism of action underlying its selective antitumor activity may be related to its regulation of Rb or Rb-associated signaling in cell cycles.

3-Hydroxycarboplatin, a Simple Carboplatin Derivative Endowed with an Improved Toxicological Profile

Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, P.R. China *Email: liguanglou1@126.com 3-Hydroxycarboplatin, a simple carboplatin derivative, was synthesised using a novel method, characterised and evaluated for its anticancer activity in vitro and in vivo. It shows comparable antitumour activity to that of carboplatin but has much lower toxicity particularly with respect to myelosuppression, revealing great potential for development as a new antitumour platinum drug to replace carboplatin.

YHHU0895, a novel synthetic small-molecule microtubule-destabilizing agent, effectively overcomes P-glycoprotein-mediated tumor multidrug resistance

P-glycoprotein-mediated multidrug resistance (MDR) is a major limiting factor in the efficacy of most microtubule-targeting agents. Here, we investigated the novel, synthetic, and small-molecule microtubule-destabilizing agent, 2-(2-amino-5-(1-ethyl-1H-indol-5-yl) pyrimidin-4-yl) phenol (YHHU0895), for its anti-tumor activity and potential for overcoming P-glycoprotein-mediated MDR. YHHU0895 inhibited purified tubulin polymerization through binding to tubulin at the colchicine-binding site and significantly inhibited human tumor cell proliferation. Notably, P-glycoprotein-overexpressing KBV200 and K562/ADR cells, which are strongly resistant to colchicine, vinorelbine and paclitaxel, were sensitive to YHHU0895 both in vitro and in vivo. These findings indicate that YHHU0895 is a novel type of microtubule-destabilizing agent that has the potential for the treatment of patients with drug resistance mediated by P-glycoprotein.

Y-632 inhibits heat shock protein 90 (Hsp90) function by disrupting the interaction between Hsp90 and Hsp70/Hsp90 organizing protein, and exerts antitumor activity in vitro and in vivo

Heat shock protein 90 (Hsp90) stabilizes a variety of proteins required for cancer cell survival and has been identified as a promising drug target for cancer treatment. To date, several Hsp90 inhibitors have entered into clinical trials, but none has been approved for cancer therapy yet. Thus, exploring new Hsp90 inhibitors with novel mechanisms of action is urgent. In the present study, we show that Y‐632, a novel pyrimidine derivative, inhibited Hsp90 in a different way from the conventional Hsp90 inhibitor geldanamycin. Y‐632 induced degradation of diverse Hsp90 client proteins through the ubiquitin–proteasome pathway, as geldanamycin did; however, it neither directly bound to Hsp90 nor inhibited Hsp90 ATPase activity. Y‐632 inhibited Hsp90 function mainly through inducing intracellular thiol oxidation, which led to disruption of the Hsp90–Hsp70/Hsp90 organizing protein complex and further induced cell adhesion inhibition, G0/G1 cell cycle arrest, and apoptosis. Moreover, Y‐632 efficiently overcame imatinib resistance mediated by Bcr‐Abl point mutations both in vitro and in vivo. We believe that Y‐632, acting as a novel small‐molecule inhibitor of the Hsp90–Hsp70/Hsp90 organizing protein complex, has great potential to be a promising Hsp90 inhibitor for cancer therapy, such as for imatinib‐resistant leukemia.

HH-GV-678, a novel selective inhibitor of Bcr-Abl, outperforms imatinib and effectively overrides imatinib resistance.

HH-GV-678, a novel selective inhibitor of Bcr-Abl, outperforms imatinib and effectively overrides imatinib resistance