In Silico Identification and In Vitro Evaluation of New ABCG2 Transporter Inhibitors as Potential Anticancer Agents

Abstract

Different molecular mechanisms contribute to the development of multidrug resistance in cancer, including increased drug efflux, enhanced cellular repair mechanisms and alterations of drug metabolism or drug targets. ABCG2 is a member of the ATP-binding cassette superfamily transporters that promotes drug efflux, inducing chemotherapeutic resistance in malignant cells. In this context, the development of selective ABCG2 inhibitors might be a suitable strategy to improve chemotherapy efficacy. Thus, through a multidisciplinary approach, we identified a new ABCG2 selective inhibitor (8), highlighting its ability to increase mitoxantrone cytotoxicity in both hepatocellular carcinoma (EC50from 8.67 ± 2.65 to 1.25 ± 0.80 μM) and transfected breast cancer cell lines (EC50from 9.92 ± 2.32 to 2.45 ± 1.40 μM). Moreover, mitoxantrone co-administration in both transfected and non-transfected HEK293 revealed that compound 8 notably lowered the mitoxantrone EC50, demonstrating its efficacy along with the importance of the ABCG2 extrusion pump overexpression in MDR reversion. These results were corroborated by evaluating the effect of inhibitor 8 on mitoxantrone cell uptake in multicellular tumor spheroids and via proteomic experiments.

A Comprehensive In Vitro Characterization of a New Class of Indole-Based Compounds Developed as Selective Haspin Inhibitors

“…As a result, compounds 47 and 60 showed a significant increase in-cell mortality when coadministered with paclitaxel 1 nM with a reduction of cell viability from 78.35 ± 1.05% (paclitaxel 1 nM alone) to 32.34 ± 1.15% ( 47 + paclitaxel 1 nM) and 50.74 ± 4.49% ( 60 + paclitaxel 1 nM, Figure A). In order to further investigate this result, we also evaluated the effect of these coadministrations on 3D cellular models, well-established models to mime tumor characteristics and for preclinical chemo-sensitivity studies. , Strong differences in spheroid mortality were already observed in the administration of compounds alone: paclitaxel (41.14 ± 2.01%) and compounds 47 (53.45 ± 8.87%) and 60 (56.85 ± 7.12%) as compared to control (22.10 ± 2.89%). Furthermore, the coadministration of paclitaxel with selected compounds led to a significant increase of cell mortality compared to compounds alone: 47 + paclitaxel induces 80.12 ± 5.32% of cell death, while 60 + paclitaxel results in 83.54 ± 7.79% of spheroids mortality (Figure B,C).…”

“…Synergistic interaction can offer several advantages: first, it allows to reduce host toxicity and side effects, given that drug doses used in combination are typically lower than that of single drugs. Additionally, it can also reduce the development of drug resistance phenomena, such as increased drug efflux ABC-transporter-mediated, enhanced cellular repair mechanisms, and alterations of drug metabolism or drug targets. , …”

“…Additionally, it can also reduce the development of drug resistance phenomena, such as increased drug efflux ABCtransporter-mediated, enhanced cellular repair mechanisms, and alterations of drug metabolism or drug targets. 51,52 Interestingly, compounds 47 and 60 showed synergy with paclitaxel both in HeLa 2D and in 3D models. Especially in the 3D model, coadministration with synthesized compounds gave a synergistic, twofold increase of the paclitaxel activity.…”

Potansiyel JNK1 İnhibe Edici Aktiviteye Sahip 2-((4-(dimetilamino)benziliden)amino)-5-metilfenol’ün Sentezi, Teorik Çalışmaları, Sitotoksisitesi

“…Chemotherapy is a standard method of cancer treatment that relies on cytotoxic drugs for the destruction or inhibition of the growth and metastasis of cancer cells. There has been a considerable effort to discover anticancer agents for cancer chemotherapy [2][3][4][5][6]. However, cancer chemotherapy often adversely affected from the chemoresistance which is the skill of tumor cells to adopt the presence of cytotoxic drugs.…”

Deciphering the functional role of clinical mutations in ABCB1, ABCC1, and ABCG2 ABC transporters in endometrial cancer

“…Usually, ATP or nucleotide binding to NBD causes conformational changes in such a manner that the substrate molecule is captured in its cavity and released on the other side. (Rees et al, 2009;Vasiliou et al, 2009;Tarling et al, 2013;Alam et al, 2019;Di et al, 2022). Of the 48 classified ABC transporters, the three most widely studied and characterized efflux glycoproteins, namely, P-glycoprotein (also known as Pgp or ABCB1), multidrug resistance protein 1 (also known as MRP1 or ABCC1), and breast cancer resistance protein (BCRP) (also known as BCRP or ABCG2), have significant roles in causing multidrug resistance in cancer.…”