Mechanism of action of the dual topoisomerase-I and -II inhibitor TAS-103 and activity against (multi)drug resistant cells

Minderman, Hans; Wrzosek, Carol; Cao, Shousong; Utsugi, Teruhiro; Kobunai, Takashi; Yamada, Yuji; Rustum, Youcef M.

doi:10.1007/pl00006747

Cited by 22 publications

(12 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Topo I, as opposed to topo II, is an enzyme that does not depend on the cellular cycle. Moreover, topo I induces cutting of only one DNA helix thread, and topo II induces cutting of one or both of them (Husain et al 1994;Son et al 1998;Minderman et al 2000). There are two isoforms of topo II, the first, topo IIa, weighs 170 kDa, and the second, topo IIß weighs 180 kDa (Krishna & Mayer 2000).…”

Section: Multidrug Resistance Associated Protein -Mrp (Mrp1)mentioning

confidence: 99%

A review of selected anti-tumour therapeutic agents and reasons for multidrug resistance occurrence

Sawicka

Kalinowska

Skierski

et al. 2004

Journal of Pharmacy and Pharmacology

View full text Add to dashboard Cite

It is assumed that proteins from the ABC family (i.e., glycoprotein P (Pgp)) and a multidrug resistance associated protein (MRP) play a main role in the occurrence of multidrug resistance (MDR) in tumour cells. Other factors that influence the rise of MDR are mechanisms connected with change in the effectiveness of the glutathione cycle and with decrease in expression of topoisomerases I and II. The aim of this review is to characterize drugs applied in anti-tumour therapy and to describe the present state of knowledge concerning the mechanisms of MDR occurrence, as well as the pharmacological agents applied in reducing this phenomenon.

show abstract

Section: Multidrug Resistance Associated Protein -Mrp (Mrp1)mentioning

confidence: 99%

A review of selected anti-tumour therapeutic agents and reasons for multidrug resistance occurrence

Sawicka

Kalinowska

Skierski

et al. 2004

Journal of Pharmacy and Pharmacology

View full text Add to dashboard Cite

show abstract

“…[4][5][6] Furthermore, TAS-103 effectively inhibited growth of tumor cells in vivo that acquire the resistance against topoisomerase II-targeting agents. [12][13][14][15] Thus, TAS-103 is expected to be used clinically. 16) Cancer chemotherapy is generally accompanied by side effects such as myelosuppression, since the cytotoxic anti-cancer agents damage normal growing cells as well as tumor cells.…”

Section: Discussionmentioning

confidence: 99%

Cancer Chemotherapy by Liposomal 6-[[2-(Dimethylamino)ethyl]amino]-3-hydroxy-7H-indeno[2,1-c]quinolin-7-one Dihydrochloride (TAS-103), a Novel Anti-cancer Agent.

Shimizu

Takada

Asai

et al. 2002

Biological & Pharmaceutical Bulletin

View full text Add to dashboard Cite

Most anti-cancer agents express not only primary therapeutic effects but also unfavorable side effects because of their low tumor-selectivity. To improve this problem, a drug delivery system (DDS) which enables delivery of a certain agent to the target organ is being used in cancer chemotherapy. Liposomes have been used as carriers of anti-cancer agents, since they can effectively deliver the entrapped materials to the interstitial spaces of tumor tissue of which blood vessels are highly permeable. Furthermore, the liposomal surface can be modified with certain targeting molecules such as antibodies and peptides, and they are expected to be used as active targeting tools.1) In fact, liposomalization of anti-tumor agents has been studied extensively and shown to increase their plasma concentration, to improve their distribution, and to decrease the side effects. 2,3) In this study, we investigated the anti-tumor efficacy of 6-[[2-(dimethylamino) ethyl]amino]-3-hydroxy-7H-indeno[2,1-c]quinolin-7-one dihydrochloride (TAS-103), a novel quinoline derivative, in a liposomal formulation. TAS-103 is known to show high and broad anti-tumor activity against murine and human tumor cells by inhibiting both topoisomerase I and II activity. [4][5][6] Like other cytotoxic anti-tumor drugs, improvement in the tumor selective delivery of the agent may make it beneficial for the practical use. For this reason, we encapsulated TAS-103 into liposomes and evaluated the antitumor efficacy of liposomal TAS-103. MATERIALS AND METHODSMaterials TAS-103 is the product of Taiho Pharmaceutical Co., Ltd. (Tokushima, Japan). Dipalmitoylphosphatidylcholine (DPPC) was a gift from Nippon Fine Chemical Co. Ltd. (Takasago, Hyogo, Japan). Cholesterol was purchased from Sigma Chemical Co. (St. Louis, MO, U.S.A.), and reduced Triton X-100 was from Aldrich Chemical Co. (Milwaukee, WI, U.S.A.).Preparation of Liposomal TAS-103 DPPC and cholesterol (2 : 1 as a molar ratio) dissolved in chloroform were dried under reduced pressure and stored in vacuo for at least 1 h to prepare thin lipid film. Liposomes were formed by hydration with 0.3 M citric acid solution adjusted to pH 4.0, frozen and thawed for three cycles using liquid nitrogen, and sonicated in a bath-type sonicator for 10 min. The resulting liposomes were sized by three extrusions through a polycarbonate membrane filter with a pore size of 100-nm. TAS-103 encapsulation was performed as described previously. 7)Briefly, liposomal solution was neutralized with 0.5 M sodium carbonate and diluted with 20 mM HEPES-buffered saline, pH 7.5, to establish a pH gradient between inner and outer solutions of liposomes. Then, the liposomes were incubated with 20 mM HEPES-buffered TAS-103 solution at 60°C for 30 min to load TAS-103 into the internal aqueous space of liposomes. Liposomal TAS-103 solution was ultracentrifuged thrice at 90000ϫg for 15 min to remove any untrapped TAS-103 if present. Then, the liposomal TAS-103 was resuspended in phosphate-buffered saline (PBS), pH 7.4. For the evaluation of encaps...

show abstract

“…The inhibitory effects of TAS-103 on topo II catalytic activity was evaluated by Minderman and co-workers. 17 They showed that TAS-103 at concentrations of 24.6 μM and higher inhibits DNA relaxation (as etoposide does) but does not cause the formation of linear DNA species as would be expected for topo II poisons. Compounds 4a,b showed the ability to inhibit enzyme activity at concentrations of 20 μM and higher without formation of linear DNA, suggesting that these compounds might be as potent as TAS-103 for catalytic topo II inhibitors.…”

Section: ■ Introductionmentioning

confidence: 94%

“…Ub possesses two potential binding sites (Met1 and His68), whereas cyt offers three (His26, His33, and Met65). Due to the fact that these samples were diluted with formic acid (0.02% (v/v)) in order to denature the present proteins, they occur in various positively charged states (Ub,(7)(8)(9)(10)(11)(12)(13)(14)cyt,(11)(12)(13)(14)(15)(16)(17)(18)(19). Therefore, deconvolution of the measured spectra was necessary.…”

Section: ■ Introductionmentioning

confidence: 99%

1,3-Dioxoindan-2-carboxamides as Bioactive Ligand Scaffolds for the Development of Novel Organometallic Anticancer Drugs

et al. 2015

View full text Add to dashboard Cite

A series of novel 1,3-dioxoindan-2-carboxamide-based complexes were synthesized, designed to employ both the attributes of half-sandwich complexes and the topoisomerase inhibiting properties of the ligand scaffold. The compounds were characterized with standard analytical methods. Their stability in aqueous systems and the impact of either the metal center or the ligand scaffold on the affinity toward small biomolecules such as amino acids, DNA model compounds, and small proteins were determined by IT-ESI mass spectrometry. The cytotoxicity was investigated in three human cancer cell lines by means of a colorimetric MTT assay, and preliminary structure−activity relationships were derived. The benzyl derivatives showed the highest in vitro activity and promising topoisomerase IIα inhibition in the range of the IC 50 values. In addition, the induced changes in the cell cycle distribution were determined and the apoptosis induction potential elucidated. ■ INTRODUCTION"Piano-stool" configured metal complexes (especially with Ru) bearing facial arene ligands have become increasingly popular among the scientific community, due to their extreme synthetic versatility and broad range of potential applications. 1 The arene represents the seat of the piano stool and the mono-or bidentate ligands the legs. Hydrolysis of the labile chlorido ligand yields positively charged aqua-complexes, which are then able to attack biological targets in the cell. 2 The coordinated aromatic system (e.g., η 6 -p-cymene (cym) and η 5 -1,2,3,4,5-pentamethylcyclopentadienyl (Cp*)) stabilizes low oxidation states of transition metals (e.g., Ru II ) and acts as a hydrophobic face, thereby enhancing cell membrane permeation. Variation of the leaving group has effects on the ligand exchange rate. 3 Complexes bearing N,N-chelates or PTA have been the most intensely studied in this compound class and are currently in an advanced preclinical stage. 4−6 Recently, bidentate ligand systems with biological activity on their own, such as flavones 7 and paullones, 8 have been employed to exploit possible synergistic effects. 9 Topoisomerases I and II (topo I and topo II) are key enzymes in DNA transcription and replication. DNA occurs in an extremely condensed form in the nucleus and needs to be uncoiled to allow the polymerase enzyme complex to read the encoded information. Uncontrolled uncoiling would involve rotations and torsions and could potentially lead to uncontrolled DNA strand breaks. Topoisomerases perform controlled single-strand breaks (isoforms of class I) or doublestrand breaks (isoforms of class II) and the respective religations. Of the two isoforms of topo II (α and β), only topo IIα plays a central role in mitosis, while topo IIβ is not imperative for cell division. 10,11 As this class of enzymes is essential for cell replication, they present an attractive point of attack for novel chemotherapeutic agents. The mechanisms of topoisomerase inhibition can be divided into two categories. The first is topoisomerase toxicity, where the topoiso...

show abstract

Mechanism of action of the dual topoisomerase-I and -II inhibitor TAS-103 and activity against (multi)drug resistant cells

Cited by 22 publications

References 16 publications

A review of selected anti-tumour therapeutic agents and reasons for multidrug resistance occurrence

A review of selected anti-tumour therapeutic agents and reasons for multidrug resistance occurrence

Cancer Chemotherapy by Liposomal 6-[[2-(Dimethylamino)ethyl]amino]-3-hydroxy-7H-indeno[2,1-c]quinolin-7-one Dihydrochloride (TAS-103), a Novel Anti-cancer Agent.

1,3-Dioxoindan-2-carboxamides as Bioactive Ligand Scaffolds for the Development of Novel Organometallic Anticancer Drugs

Contact Info

Product

Resources

About