Selective cellular uptake and retention of SN 28049, a new DNA-binding topoisomerase II-directed antitumor agent

Chen, Ying Yi; Lukka, Pradeep B.; Joseph, Wayne R.; Finlay, Graeme J.; Paxton, James W.; McKeage, Mark J.; Baguley, Bruce C.

doi:10.1007/s00280-014-2469-x

Cited by 8 publications

(8 citation statements)

References 34 publications

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“…In our [Koshkin et al, ] and others' [ Kars et al, ; Zhang et al, ] previous studies, it was found that intrinsic MDR in MCF‐7 cells is supported by the MRP1 transporter. Therefore, loaded cells were incubated for 60 min with an antibody for the extracellular domain of MRP1 (IU2H10 1:100 50 μg/mL, Novus Biologicals, Littleton, CO) [Binyamin et al, ; Chen et al, ]. Fluorescence labeling of the transporter was achieved by addition of the secondary antibody, FITC‐labeled anti mouse IgG (R1253F from Acris Antibodies, San Diego, CA), according to manufacturer's instructions.…”

Section: Methodsmentioning

confidence: 99%

Metabolic Suppression of a Drug‐Resistant Subpopulation in Cancer Spheroid Cells

Koshkin

Ailles

Liu³

et al. 2015

J of Cellular Biochemistry

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Inhibition of metabolic features which distinguish cancer cells from their non-malignant counterparts is a promising approach to cancer treatment. Energy support for drug extrusion in multidrug resistance (MDR) is a potential target for metabolic inhibition. Two major sources of ATP-based metabolic energy are partial (glycolysis) and complete (mitochondrial oxidative phosphorylation) oxidation of metabolic fuels. In cancer cells, the balance between them tends to be shifted toward glycolysis; this shift is considered to be characteristic of the cancer metabolic phenotype. Numerous earlier studies, conducted with cells cultured in a monolayer (2-D model), suggested inhibition of glycolytic ATP production as an efficient tool to suppress MDR in cancer cells. Yet, more recent work challenged the appropriateness of the 2-D model for such studies and suggested that a more clinically relevant approach would utilize a more advanced cellular model such as a 3-D model. Here, we show that the transition from the 2-D model (cultured monolayer) to a 3-D model (cultured spheroids) introduces essential changes into the concept of energetic suppression of MDR. The 3-D cell organization leads to the formation of a discrete cell subpopulation (not formed in the 2-D model) with elevated MDR transport capacity. This subpopulation has a specific metabolic phenotype (mixed glycolytic/oxidative MDR support) different from that of cells cultured in the 2-D model. Finally, the shift to the oxidative phenotype becomes greater when the spheroids are grown under conditions of lactic acidosis that are typical for solid tumors. The potential clinical significance of these findings is discussed.

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Section: Methodsmentioning

confidence: 99%

Metabolic Suppression of a Drug‐Resistant Subpopulation in Cancer Spheroid Cells

Koshkin

Ailles

Liu³

et al. 2015

J of Cellular Biochemistry

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“…In this regard, acridine is a potential bioactive molecule, and many of its derivatives are extensively studied for their antibacterial, antimalarial, and anticancer activities. − Besides, the planer structure of acridine allows it to intercalate with DNA and inhibit the topoisomerase-II enzyme. , These findings provided the opportunity to design acridine-based photocages for targeted control release of anticancer drugs. Zhuang and co-workers first introduced 9-hydroxymethylacridine chromophore as a photocage for different alcohols .…”

Section: Introductionmentioning

confidence: 99%

Visible Light-Responsive Delivery of Two Anticancer Drugs Using Single-Component Fluorescent Organic Nanoparticles

Ray

Banerjee

Singh

et al. 2022

ACS Appl. Nano Mater.

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Combination therapy is a promising strategy to improve therapeutic efficiency and minimize side effects. So far, the C9-functionalized acridine derivatives were employed as photocages to deliver only one active molecule. Here, we have developed a C4, C5-substituted dual-arm acridine photocage for the first time to release two carboxylic acids and amino acids simultaneously. As a proof of concept, we have constructed a visible light-responsive dual drug delivery system (Acr-Cbl-Vpa) and made it single-component fluorescent organic nanoparticles (NPs) to deliver two anticancer drugs (chlorambucil and valproic acid). Acr-Cbl-Vpa NPs can accumulate inside the cell nucleus, and the planer motif allows the photocage to intercalate with the DNA and maximize the cancer cell killing ability of the drugs. In vitro studies with cancerous HeLa cell lines showed that Acr-Cbl-Vpa NPs displayed improved anticancer efficacy and real-time fluorescence monitoring of the drug release.

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“…Quantification of cellular uptake of drugs is very important for assessing their anti-tumor effect [27,28,29], where fluorescence-based methods offer several advantages such as high sensitivity, fast and easy operation [30,31]. EVO and RUT are derivatives of the quino[2′,3′-3,4]pyrrolo-[2,1- b ]quinazoline ring system whose structures comprise a quinoline ring system, a pyridone ring and a terminal hydroxylactone ring (Scheme 1), similar to the strong topoisomerase I inhibitor luotonin A and anticancer drug camptothecin [32,33].…”

Section: Introductionmentioning

confidence: 99%

Antiproliferative Activity and Cellular Uptake of Evodiamine and Rutaecarpine Based on 3D Tumor Models

Guo

Gao

et al. 2016

Molecules

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Evodiamine (EVO) and rutaecarpine (RUT) are promising anti-tumor drug candidates. The evaluation of the anti-proliferative activity and cellular uptake of EVO and RUT in 3D multicellular spheroids of cancer cells would better recapitulate the native situation and thus better reflect an in vivo response to the treatment. Herein, we employed the 3D culture of MCF-7 and SMMC-7721 cells based on hanging drop method and evaluated the anti-proliferative activity and cellular uptake of EVO and RUT in 3D multicellular spheroids, and compared the results with those obtained from 2D monolayers. The drugs' IC 50 values were significantly increased from the range of 6.4-44.1 µM in 2D monolayers to 21.8-138.0 µM in 3D multicellular spheroids, which may be due to enhanced mass barrier and reduced drug penetration in 3D models. The fluorescence of EVO and RUT was measured via fluorescence spectroscopy and the cellular uptake of both drugs was characterized in 2D tumor models. The results showed that the cellular uptake concentrations of RUT increased with increasing drug concentrations. However, the EVO concentrations uptaken by the cells showed only a small change with increasing drug concentrations, which may be due to the different solubility of EVO and Rut in solvents. Overall, this study provided a new vision of the anti-tumor activity of EVO and RUT via 3D multicellular spheroids and cellular uptake through the fluorescence of compounds.

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Selective cellular uptake and retention of SN 28049, a new DNA-binding topoisomerase II-directed antitumor agent

Abstract: The results suggest that SN 28049 is actively transported into cytoplasmic vesicles. While vesicle-associated drug is not important for intrinsic cytotoxicity, it may play a key role as a "slow release" form that modifies pharmacokinetics in multicellular structures such as tumours.

Cited by 8 publications

References 34 publications

Metabolic Suppression of a Drug‐Resistant Subpopulation in Cancer Spheroid Cells

Metabolic Suppression of a Drug‐Resistant Subpopulation in Cancer Spheroid Cells

Visible Light-Responsive Delivery of Two Anticancer Drugs Using Single-Component Fluorescent Organic Nanoparticles

Antiproliferative Activity and Cellular Uptake of Evodiamine and Rutaecarpine Based on 3D Tumor Models

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