Selective induction of tumor cell apoptosis by a novel P450-mediated reactive oxygen species (ROS) inducer methyl 3-(4-nitrophenyl) propiolate.

Induction of tumor cell apoptosis has been recognized as a valid anticancer strategy. However, therapeutic selectivity between tumor and normal cells has always been a challenge. Here, we report a novel anti-cancer compound methyl 3-(4-nitrophenyl) propiolate (NPP) preferentially induces apoptosis in tumor cells through P450-catalyzed reactive oxygen species (ROS) production. A compound sensitivity study on multiple cell lines shows that tumor cells with high basal ROS levels, low antioxidant capacities, and p53 mutations are especially sensitive to NPP. Knockdown of p53 sensitized non-transformed cells to NPP-induced cell death. Additionally, by comparing NPP with other ROS inducers, we show that the susceptibility of tumor cells to the ROS-induced cell death is influenced by the mode, amount, duration, and perhaps location of ROS production. Our studies not only discovered a unique anticancer drug candidate but also shed new light on the understanding of ROS generation and function and the potential application of a ROS-promoting strategy in cancer treatment.

Discovery of novel 2-N-aryl-substituted benzenesulfonamidoacetamides: orally bioavailable tubulin polymerization inhibitors with marked antitumor activities.

The discovery and optimization of a series of 2-N-aryl-substituted benzenesulfonamidoacetamides as novel tubulin polymerization inhibitors are described. Pharmacophore exploration of hit compound AH-487 identified the optimal structure of N-heteroaryl-2-(4-methoxy-N-(3-(trifluoromethyl)phenyl)phenylsulfonamido)acetamide as a potent antimitotic agent. Subsequent lead compounds 4b and 4c, with N-4-aminophenyl and N-1H-indol-5-yl substitutions at the acetamide position, respectively, were shown to induce cell-cycle arrest at the G(2) /M phase and lead to an accumulation of HeLa cells in the sub-G(1) phase. More significantly, these lead compounds (3c, 4b, and 4c) exhibit impressive cytotoxicity against a panel of cancer cells including P-glycoprotein-overexpressing MDR-positive cells, with potency greater than or equal to clinically studied benzenesulfonamide E7010. Mechanistic studies demonstrated that derivatives of AH-487 disrupt mitotic spindles by inhibiting microtubule polymerization and induce apoptosis via induction of Bcl-2 phosphorylation in tumor cells. The optimized leads 4b and 4c strongly inhibited the growth of human hepatocellular carcinoma cells in a mouse xenograft model.

A novel synthetic analog of 5, 8-disubstituted quinazolines blocks mitosis and induces apoptosis of tumor cells by inhibiting microtubule polymerization.

Many mitosis inhibitors are powerful anticancer drugs. Tremendous efforts have been made to identify new anti-mitosis compounds for developing more effective and less toxic anti-cancer drugs. We have identified LJK-11, a synthetic analog of 5, 8-disubstituted quinazolines, as a novel mitotic blocker. LJK-11 inhibited growth and induced apoptosis of many different types of tumor cells. It prevented mitotic spindle formation and arrested cells at early phase of mitosis. Detailed in vitro analysis demonstrated that LJK-11 inhibited microtubule polymerization. In addition, LJK-11 had synergistic effect with another microtubule inhibitor colchicine on blocking mitosis, but not with vinblastine or nocodazole. Therefore, LJK-11 represents a novel anti-microtubule structure. Understanding the function and mechanism of LJK-11 will help us to better understand the action of anti-microtubule agents and to design better anti-cancer drugs.

4'-Alkoxyl substitution enhancing the anti-mitotic effect of 5-(3',4',5'-substituted)anilino-4-hydroxy-8-nitroquinazolines as a novel class of anti-microtubule agents.

Mitosis inhibitors are powerful anticancer drugs. Based on a novel anti-microtubule agent of 5-(4'-methoxy)anilino-4-hydroxy-8-nitroquinazoline, a series of 5-(3',4',5'-substituted)anilino-4-hydroxy-8- nitroquinazolines were designed and synthesized to investigate the effect of the substitution on the inhibitory activity against mitotic progression of tumor cells. The large alkoxyl substitution on the 4'-position of 5-anilino ring is beneficial for the potency. The 5-(3',4',5'-trimethoxy)anilino-8-nitroquinazoline (1h) displays an overwhelming activity in arresting the cells at the G2/M phase, providing a promising new template for further development of potent microtubule-targeted anti-mitotic drugs.

[Protective effect of berberine on cardiac hypertrophy induced by L-thyroxine in rats].

OBJECTIVE: To assess the effects of berberine on cardiac hypertrophy induceded by L-thyroxine(L-Thy) in rats. METHODS: A cardiac hypertrophy model was produced by intraperitoneal (i.p.) injection of L-thyroxine 0.5 mg/(kg.d) x 10 d. 24 SD rats were divided into three groups: 1. control (normal saline); 2. L-Thy; 3. i.p. L-Thy + berberine gastrogavage 30 mg/(kg.d) x 10 d. Then the cardiac indexes, Na(+)-K(+)-ATPase activity, Ca(2+)-ATPase activity, the cardiac nitric oxide (NO) content, and the CaN activity were measured. RESULTS: Compared with the measurements in the control group, the cardiac indexes and the CaN activity were remarkably increased in the hypertrophy group (P < 0.01), but the cardiac NO content, Na(+)-K(+)-ATPase activity and Ca(2+)-ATPase activity in myocardium were significantly decreased (P < 0.01). Further comparison between the hypertrophy group and the L-Thy + berberine group showed that berberine 30 mg/(kg.d) x 10 d prevented the ventricular hypertrophy induced by L-Thy and decreased the cardiac indexes and CaN activity (P < 0.01); berberine elevated the cardiac NO content, Na(+)-K(+)-ATPase activity and Ca(2+)-ATPase activity (P < 0.01). CONCLUSION: Berberine can prevent the cardiac hypertrophy induced by L-thyroxine in rats.