Uptake and efflux of FL118 and two FL118 derivatives in 3D cell model

Zhou, Leilei; Weng, Qi; Zheng, Yixin; Zhou, Yuqin; Li, Qingyong; Li, Fengzhi

doi:10.1007/s10616-019-00322-5

Cited by 9 publications

(9 citation statements)

References 19 publications

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“…It turned out that while each of the five compounds show significant antitumor activity, FL118 was the top compound, possessing exceptional efficacy to eliminate human xenograft tumor without relapse over a period of 60 days in a high percentage of human tumors in animal models [63,68]. Interestingly, 3-dimentional (3D) cell models were recently developed for testing FL118 and several of the FL118 analogs [69,70]. However, whether the 3D cell models could replace the early stage in vivo animal testing for cost-effectiveness and selection of the future FL118 analogs remains to be investigated.…”

Section: Fl118mentioning

confidence: 99%

Cancer therapeutics using survivin BIRC5 as a target: what can we do after over two decades of study?

Aljahdali

Ling

2019

J Exp Clin Cancer Res

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185

171

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Survivin (also named BIRC5) is a well-known cancer therapeutic target. Since its discovery more than two decades ago, the use of survivin as a target for cancer therapeutics has remained a central goal of survivin studies in the cancer field. Many studies have provided intriguing insight into survivin's functional role in cancers, thus providing promise for survivin as a cancer therapeutic target. Despite this, moving survivin-targeting agents into and through the clinic remains a challenge. In order to address this challenge, we may need to rethink current strategies in order to develop a new mindset for targeting survivin. In this Review, we will first summarize the current survivin mechanistic studies, and then review the status of survivin cancer therapeutics, which is classified into five categories: (i) survivin-partner protein interaction inhibitors, (ii) survivin homodimerization inhibitors, (iii) survivin gene transcription inhibitors, (iv) survivin mRNA inhibitors and (v) survivin immunotherapy. We will then provide our opinions on cancer therapeutics using survivin as a target, with the goal of stimulating discussion that might facilitate translational research for discovering improved strategies and/or more effective anticancer agents that target survivin for cancer therapy.

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Section: Fl118mentioning

confidence: 99%

Cancer therapeutics using survivin BIRC5 as a target: what can we do after over two decades of study?

Aljahdali

Ling

2019

J Exp Clin Cancer Res

Self Cite

185

171

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“…These 7-substitution-FL118 analogues FL77-1–FL77-24 exhibited a stronger ability to inhibit cancer cell growth than their corresponding 9-substitution FL118 analogues ( FL97-1–FL97-24 ) (Table ). One possibility may be attributed to the different cellular permeabilities of the FL118 position 7 analogues versus position 9 compounds − (See other possibilities discussed in the “Discussion” section). Many compounds from FL77-1–FL77-24 exhibited anticancer cell growth ability comparable to their parental compound FL118, and some of them exhibited significantly better anticancer cell growth ability than FL118 (Table ).…”

Section: Resultsmentioning

confidence: 99%

Structure–Activity Relationship of FL118 Platform Position 7 Versus Position 9-Derived Compounds and Their Mechanism of Action and Antitumor Activity

Wang,

Ling,

Wang

et al. 2023

J. Med. Chem.

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“…Given that FL118 was a promising anti-tumor molecule, a series of C7-and C9-substituted compounds using FL118 as the platform were synthesized by our group [23,28,29]. In this work, the results of the MTT assay demonstrated that FL77-28 and FL77-29 were more potent than FL118 in HCT 116, Hep G2, and HeLa cell lines, which was consistent with the MTT results of another C7 fluorinated benzene substituent, 7Q-20, showing superior anti-tumor activity with IC 50 at the nM level.…”

Section: Discussionmentioning

confidence: 99%

“…The cytotoxicity of FL118, FL77-28, and FL77-29 against HCT116, HeLa, A549 HepG2, and Caco-2 cell lines were measured using MTT assays [23]. The cells were plated into 96-well plates at a density of 2 × 10 4 cells/mL and cultured for 24 h. Next, the cells were treated with 0.0125-0.500 µM of FL118, FL77-28, and FL77-29 for 4 h or 72 h. After incubation with 20 µL of 5 mg/mL MTT solution for 4 h, the supernatant was gently discarded and 150 µL of DMSO was added to dissolve the formazan crystals.…”

Section: Cytotoxicity Assaymentioning

confidence: 99%

Investigation of the Uptake and Transport of Two Novel Camptothecin Derivatives in Caco-2 Cell Monolayers

et al. 2022

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Irinotecan and Topotecan are two Camptothecin derivatives (CPTs) whose resistance is associated with the high expression of breast cancer resistance protein (BCRP) and P-glycoprotein (P-gp). To reverse this resistance, two novel CPTs, FL77-28 (7-(3-Fluoro-4-methylphenyl)-10,11-methylenedioxy-20(S)-CPT) and FL77-29 (7-(4-Fluoro-3-methylphenyl)-10,11-methylenedioxy-20(S)-CPT), were synthesized by our group. In this study, the anti-tumor activities of FL77-28, FL77-29, and their parent, FL118 (10,11-methylenedioxy-20(S)-CPT), were evaluated and the results showed that FL77-28 and FL77-29 had stronger anti-tumor activities than FL118. The transport and uptake of FL118, FL77-28, and FL77-29 were investigated in Caco-2 cells for the preliminary prediction of intestinal absorption. The apparent permeability coefficient from apical to basolateral (Papp AP-BL) values of FL77-28 and FL77-29 were (2.32 ± 0.04) × 10−6 cm/s and (2.48 ± 0.18) × 10−6 cm/s, respectively, suggesting that the compounds had moderate absorption. Since the transport property of FL77-28 was passive diffusion and the efflux ratio (ER) was less than 2, two chemical inhibitors were added to further confirm the involvement of efflux proteins. The results showed that FL77-28 was not a substrate of P-gp or BCRP, but FL77-29 was mediated by P-gp. In conclusion, FL77-28 might be a promising candidate to overcome drug resistance induced by multiple efflux proteins.

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Uptake and efflux of FL118 and two FL118 derivatives in 3D cell model

Cited by 9 publications

References 19 publications

Cancer therapeutics using survivin BIRC5 as a target: what can we do after over two decades of study?

Cancer therapeutics using survivin BIRC5 as a target: what can we do after over two decades of study?

Structure–Activity Relationship of FL118 Platform Position 7 Versus Position 9-Derived Compounds and Their Mechanism of Action and Antitumor Activity

Investigation of the Uptake and Transport of Two Novel Camptothecin Derivatives in Caco-2 Cell Monolayers

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