7-ethyl-7-hydroxy-10h-1-3-dioxolo(4-5-g)pyrano(3--4--6-7)indolizino(1-2-b)quinoline-8-11(7h-12h)-dione and Neoplasms

Nanomedicines have shown success in cancer therapy in recent years because of their excellent solubility in aqueous solution and drug accumulation through controlled release in tumor tissues, but the preparation of most nanomedicines still requires ionic materials, surfactants or the amphiphilic structure to maintain nanoparticle stability and function. In this study, we developed a couple of novel dually hydrophobic prodrugs (DHPs) by combining two hydrophobic compounds through different linkers and elaborated their self-assembly mechanisms by virtue of computational simulation. Importantly, without using any excipients, FL-2 NPs exhibited significantly prolonged retention in blood circulation and displayed a remarkable anti-tumor effect at very low concentration in vivo. Both DHPs consisted of camptothecin structural analogue(FL118) and a marine natural product (ES-285). Comparative experiments proved that these compounds could quickly form nanoparticles by way of simple preparation and remained relatively stable for long periods in PBS. FL-2 NPs linked with a disulphide bond could rapidly release bioactive FL118 after being triggered by endogenous reductive stimulus to exert anti-cancer effects. Overall, this study provides a new strategy for design of therapeutic nanomedicines consisting of dually hydrophobic molecules for cancer therapy.

Topics: Animals; Benzodioxoles; Camptothecin; Chromones; Disulfides; Drug Stability; Humans; Hydrophobic and Hydrophilic Interactions; Indolizines; Lipids; Nanomedicine; Nanoparticles; Neoplasms; Prodrugs

A novel camptothecin analogue, (20S)-10,11-methylenedioxy-camptothecin (FL118), has been proven to show significant antitumor efficacy for a wide variety of solid tumors. However, the further development of FL118 is severely hindered due to its extremely poor water solubility and adverse side effects. Here, two series of novel 20-substituted (20S)-10,11-methylenedioxy-camptothecin coupled with 5-substituted uracils and other heterocyclic rings through glycine were synthesized. All the derivatives showed superior cytotoxic activities in vitro with IC

Topics: A549 Cells; Animals; Antineoplastic Agents; Apoptosis; Benzodioxoles; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Hep G2 Cells; HL-60 Cells; Humans; Indolizines; Irinotecan; K562 Cells; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasms; Transcription, Genetic

Recent researches are attempting to verify that the 3D cell models can provide a gap bridge between in vitro and in vivo for anticancer drug evaluations. The aim of this study was to continue the development of novel in vitro 3D cell models and the investigation of the cellular uptake mechanism of camptothecin (CPT) and its derivatives [FL118 (10,11-methylenedioxy-20(S)-camptothecin), 9-Q20 (9-p-trifluoromethylphenyl-10,11-methylenedioxy-20(S)-camptothecin)] in 2D and 3D cell models.. The 3D cell models were established using ultralow attachment 96-well plates. The cytotoxicity of CPT, FL118, and 9-Q20 was evaluated by MTT method. The effects of compound concentration, incubation time, temperature, and transporter inhibitors on the cellular uptake of CPT, FL118, and 9-Q20 were examined in 2D and 3D cell models.. The cytotoxicity of CPT, FL118, and 9-Q20 was lower in 3D cell models than 2D cell models. In 2D Caco-2 cell model, the uptake rate of CPT, FL118, and 9-Q20 was faster during the early time of incubation. In 3D Caco-2 cell model, the uptake capacity of CPT, FL118, and 9-Q20 was significantly improved over time. In 3D Caco-2 cell model, Verapamil (P-gp inhibitor) and Gefitinib (BCRP inhibitor) more significantly increased the uptake of CPT and 9-Q20. In contrast, P-gp and BCRP did not affect the accumulation of FL118 in 2D and 3D Caco-2 cell models. The accumulation of CPT, FL118, and 9-Q20 was greater in HepG2 cells than HCT116 cells.. The 3D cell models provided more potency information on the process of cellular uptake of CPT, FL118, and 9-Q20, which more objectively reflected the drug sensitivity and drug resistance in vivo compared with the 2D cell models.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Benzodioxoles; Biological Transport; Camptothecin; Cell Proliferation; HCT116 Cells; Hep G2 Cells; Humans; In Vitro Techniques; Indolizines; Neoplasms

Drug/radiation resistance to treatment and tumor relapse are major obstacles in identifying a cure for cancer. Development of novel agents that address these challenges would therefore be of the upmost importance in the fight against cancer. In this regard, studies show that the antiapoptotic protein survivin is a central molecule involved in both hurdles. Using cancer cell-based survivin-reporter systems (US 7,569,221 B2) via high throughput screening (HTS) of compound libraries, followed by in vitro and in vivo analyses of HTS-derived hit-lead compounds, we identified a novel anticancer compound (designated FL118). FL118 shows structural similarity to irinotecan. However, while the inhibition of DNA topoisomerase 1 activity by FL118 was no better than the active form of irinotecan, SN-38 at 1 µM, FL118 effectively inhibited cancer cell growth at less than nM levels in a p53 status-independent manner. Moreover, FL118 selectively inhibited survivin promoter activity and gene expression also in a p53 status-independent manner. Although the survivin promoter-reporter system was used for the identification of FL118, our studies revealed that FL118 not only inhibits survivin expression but also selectively and independently inhibits three additional cancer-associated survival genes (Mcl-1, XIAP and cIAP2) in a p53 status-independent manner, while showing no inhibitory effects on control genes. Genetic silencing or overexpression of FL118 targets demonstrated a role for these targets in FL118's effects. Follow-up in vivo studies revealed that FL118 exhibits superior antitumor efficacy in human tumor xenograft models in comparison with irinotecan, topotecan, doxorubicin, 5-FU, gemcitabine, docetaxel, oxaliplatin, cytoxan and cisplatin, and a majority of mice treated with FL118 showed tumor regression with a weekly × 4 schedule. FL118 induced favorable body-weight-loss profiles (temporary and reversible) and was able to eliminate large tumors. Together, the molecular targeting features of FL118 plus its superior antitumor activity warrant its further development toward clinical trials.

Topics: Animals; Antineoplastic Agents; Apoptosis; Benzodioxoles; Cell Line, Tumor; Cell Proliferation; DNA Topoisomerases, Type I; Drug Screening Assays, Antitumor; Female; Gene Expression Regulation, Neoplastic; High-Throughput Screening Assays; Humans; Indolizines; Inhibitor of Apoptosis Proteins; Maximum Tolerated Dose; Mice; Mice, Nude; Mice, SCID; Myeloid Cell Leukemia Sequence 1 Protein; Neoplasms; Promoter Regions, Genetic; Proto-Oncogene Proteins c-bcl-2; Survivin; Tumor Burden; Tumor Suppressor Protein p53; X-Linked Inhibitor of Apoptosis Protein; Xenograft Model Antitumor Assays