Potent antitumor activity of 10-methoxy-9-nitrocamptothecin

Luo, Peihua; He, Qiaojun; He, Xiao‐Gang; Hu, Yongzhou; Lü, Wei; Cheng, Yiyu; Yang, Bo

doi:10.1158/1535-7163.mct-05-0385

Cited by 28 publications

(10 citation statements)

References 25 publications

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“…The mechanism of anti-tumor activity of MONCPT is associated with antiangiogenesis response and regulation of cell cycle described previously by us (7,8). Our results here demonstrated that MONCPT encapsulated in nano-carrier did not change the effect on cell cycle induced by drug itself.…”

Section: Discussionsupporting

confidence: 78%

“…We have studied both in vitro and in vivo anti-tumor activity of MONCPT on A549 cells as reported (8), and then focus our present study (such as anti-tumor activity) on the S180 tumor.…”

Section: Discussionmentioning

confidence: 99%

“…However, 9-nitrocamptothecin was difficult to prepare by nitration of camptothecin because 12-nitrocamptothecin was the main product (4). In contrast, 10-alkoxy-9-nitrocamptothecin (MONCPT) could easily be prepared from 10-hydroxycamptothecin (5,6), which possesses a potent anti-tumor activity due to its regulation of cell cycle or potential property for inhibiting angiogenesis as revealed in our previous studies (7,8). However, poor solubility and stability of MONCPT like other camptothecin derivatives limits its further in vivo researches.…”

Section: Introductionmentioning

confidence: 98%

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A Novel Camptothecin Derivative Incorporated in Nano-Carrier Induced Distinguished Improvement in Solubility, Stability and Anti-tumor Activity Both In Vitro and In Vivo

Han

Fang

et al. 2008

Pharm Res

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Purpose. An oil/water nanoemulsion was developed in the present study to enhance the solubility, stability and anti-tumor activity of a novel 10-methoxy-9-nitrocamptothecin (MONCPT). Materials and Methods. MONCPT nanoemulsion was prepared using Lipoid E80 and cremophor EL as main emulsifiers by microfluidization. The droplet size of the nanoemulsion was measured by dynamic light scattering. In vitro drug release was monitored by membrane dialysis. Kinetics of MONCPT transformed into carboxylic salt was performed in phosphate buffer at different pH. Hemolysis of MONCPT nanoemulsion was conducted in rabbit erythrocytes. Solubilization character of MONCPT in nanoemulsion was experimented using Nile red as a solvatochromic probe. In vitro cytotoxicity of the nanoemulsion was measured in A549 and S180 cells using Sulforhodamine B protein stain method, and suppression rate of tumor growth was investigated in S180-bearing mice. The cell cycle effects of MONCPT nanoemulsion on S180 cells were analyzed by flow cytometry. Distribution of the nanoemulsion in A549 cells and S180-bearing mice were also investigated by fluorescence image. Results. MONCPT is incorporated in the nanoemulsion in form of lactone with concentration of 489 µg/ml, more than 200 folds higher than that in water. Experiments using Nile red as a solvatochromic probe indicated that more MONCPT might be located in the interfacial surfactant layer of the nanoemulsion than that in discrete oil droplet or continuous aqueous phase. Nanoemulsion could release MONCPT in a sustained way, and it was further shown to notably postpone the hydrolysis of MONCPT with longer hydrolysis half-life time (11.38 h) in nanoemulsion at pH 7.4 than that of MONCPT solution (4.03 h). No obvious hemolysis was caused by MOCPT nanoemulsion in rabbit erythrocytes. MONCPT nanoemulsion showed a marked increase in cytotoxic activity, 23.6 folds and 28.6 folds in S180 cells and A549 cells respectively via arresting the cell at G2 phase, compared to that induced by MONCPT injection. It correlated well to the in vivo anti-tumor activity of MONCPT nanoemulsion with suppression rate of 93.6%, while that of MONCPT injection was only 24.2% at the same dosage. Moreover, nanoemulsion exhibited enhanced capability of delivering drug into malignant cell's nucleus in vitro and induced drug accumulation in tumor in S180-bearing mice using in vivo imaging. Conclusion. The nanoemulsion prepared exhibited an improved MONCPT solubility, stability and antitumor activity, providing a promising carrier for cancer chemotherapy using MONCPT.

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Section: Discussionsupporting

confidence: 78%

“…We have studied both in vitro and in vivo anti-tumor activity of MONCPT on A549 cells as reported (8), and then focus our present study (such as anti-tumor activity) on the S180 tumor.…”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

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A Novel Camptothecin Derivative Incorporated in Nano-Carrier Induced Distinguished Improvement in Solubility, Stability and Anti-tumor Activity Both In Vitro and In Vivo

Han

Fang

et al. 2008

Pharm Res

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“…We analyzed the possible alterations of cell cycle regulators reported to play important roles in the regulation of the G 0 /G 1 phase [20] . Figure 5 shows that the level of p21 CIP1 changed with increases in the concentration of …”

Section: Chamaejasmenin B and Neochamaejasmin C Induced Apoptosismentioning

confidence: 99%

In vitro anti-cancer activity of chamaejasmenin B and neochamaejasmin C isolated from the root of Stellera chamaejasme L

et al. 2012

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Aim: To examine the anti-cancer effects of chamaejasmenin B and neochamaejasmin C, two biflavonones isolated from the root of Stellera chamaejasme L (known as the traditional Chinese herb Rui Xiang Lang Du) in vitro. Methods: Human liver carcinoma cell lines (HepG2 and SMMC-7721), a human non-small cell lung cancer cell line (A549), human osteosarcoma cell lines (MG63, U2OS, and KHOS), a human colon cancer cell line (HCT-116) and a human cervical cancer cell line (HeLa) were used. The anti-proliferative effects of the compounds were measured using SRB cytotoxicity assay. DNA damage was detected by immunofluorescence and Western blotting. Apoptosis and cell cycle distribution were assessed using flow cytometry analysis. The expression of the related proteins was examined with Western blotting analysis. Results: Both chamaejasmenin B and neochamaejasmin C exerted potent anti-proliferative effects in the 8 human solid tumor cell lines. Chamaejasmenin B (the IC 50 values ranged from 1.08 to 10.8 μmol/L) was slightly more potent than neochamaejasmin C (the IC 50 values ranged from 3.07 to 15.97 μmol/L). In the most sensitive A549 and KHOS cells, the mechanisms underlying the anti-proliferative effects were characterized. The two compounds induced prominent expression of the DNA damage marker γ-H2AX as well as apoptosis. Furthermore, treatment of the cells with the two compounds caused prominent G 0 /G 1 phase arrest. Conclusion: Chamaejasmenin B and neochamaejasmin C are potential anti-proliferative agents in 8 human solid tumor cell lines in vitro via inducing cell cycle arrest, apoptosis and DNA damage.

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“…21) The results are summarized in Table 1. As outlined in Table 1, most tested compounds exhibited cytotoxic activity against HL60 cell, especially 6dc (IC 50 is 0.46 mM).…”

Section: Resultsmentioning

confidence: 99%

Synthesis and Cytotoxicity of Indolopyrrolemaleimides

Guo

Zhang

et al. 2007

CHEMICAL & PHARMACEUTICAL BULLETIN

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Cancer is the second leading cause of death in the world. Currently, there are many different targets in cancer chemotherapy. Among them, DNA topoisomerase I has been shown to be an important target. [1][2][3][4] The development of DNA topoisomerase I inhibitors as cancer chemotherapy agents is currently an active area of research.5) Indolocarbazoles including NB-506 and rebeccamycin exhibit antitumor properties very likely via topoisomerase I inhibition. To improve their cytotoxicitives, various modifications were performed. [6][7][8][9][10] In addition, many bisarylmaleimide compounds, which were prepared by replaceing one of the indolo groups with other aryl/heteroarylcycle, exhibited remarkable cancer cells poisons. [11][12][13][14] These prompted us to design a new series of bisindolomaleimide ( Fig. 1) analogues in order to find more potent cytotoxic compounds and to carry out a structure-activity relationship study. Because pyrrole is a pharmacophore with many biological properties, it was chosen to replace one of the indolo groups of bisindolomaleimides. In this paper, we describe the synthesis of the indolopyrrolemaleimide derivatives 6 and 11 ( Fig. 1), the evaluation of these compounds as topoisomerase I inhibitor, and their cytotoxic activity in vitro against various human cancer cell lines. Results and DiscussionThe general synthetic approach to the indolopyrrolemaleimides 6 is outlined in Chart 1. Indole adducts 3a-d were prepared starting from appropriate indole. 15,16) The NH of indole adducts 3a-d were protected by di-tert-butyl dicarbonate ((Boc) 2 O) to form the key intermediates 4a-d. 5a-d were prepared by reacting pyrrole with 4a-d using lithium hexamethyldisilazide (LiHMDS) as a base. Deprotection of BOC groups of 5a-d with methylamine or ethylamine afforded 6ac, 6bc, 6cc, 6dc, 6ad, 6bd, 6cd and 6dd, respectively. 17) Treatment 5a with ammonium acetate (NH 4 OAc) yielded 6aa and 6ab (1 : 1). Similarly, treatment 5b or 5c with NH 4 OAc got 6ba and 6bb or 6ca and 6cb, respectively. 17,18) Preparation of compounds 11 were performed according to the procedure of Chart 2. Treating 3a or 3b with methylamine afforded 7a or 7b. 8a or 8b was prepared by protecting the NH of 7a or 7b with (Boc) 2 O, and then condensation of 8a or 8b with pyrrole obtained 9a or 9b. 17) Treating 9a or 9b with KOH-dioxane achieved 10a or 10b [17][18][19] which were converted to indolopyrrolemaleimide compounds 11 by treating with various compounds containing-NH 2 . 20)All the prepared compounds were evaluated for their cytotoxicity against cancer cells in vitro.First, compounds 6 were evaluated for their cytotoxic activity in vitro against human leukemia cell line (HL60), and four human solid cancer cell lines: human prostate cancer cell line (PC-3), human esophageal cancer cell line (ECA-109), human liver cancer cell line (Bel-7402) and non-smallcell lung cancer cell line (A549) according to the reported methods.21) The results are summarized in Table 1. As outlined in Table 1, most tested compounds exhibited cytotoxic...

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Potent antitumor activity of 10-methoxy-9-nitrocamptothecin

Cited by 28 publications

References 25 publications

A Novel Camptothecin Derivative Incorporated in Nano-Carrier Induced Distinguished Improvement in Solubility, Stability and Anti-tumor Activity Both In Vitro and In Vivo

A Novel Camptothecin Derivative Incorporated in Nano-Carrier Induced Distinguished Improvement in Solubility, Stability and Anti-tumor Activity Both In Vitro and In Vivo

In vitro anti-cancer activity of chamaejasmenin B and neochamaejasmin C isolated from the root of Stellera chamaejasme L

Synthesis and Cytotoxicity of Indolopyrrolemaleimides

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