Dual P-Glycoprotein and CA XII Inhibitors: A New Strategy to Reverse the P-gp Mediated Multidrug Resistance (MDR) in Cancer Cells

A new series of N,N-bis(alkanol)amine aryl diesters was synthesized and studied as dual P-glycoprotein (P-gp) and carbonic anhydrase XII inhibitors (CA XII). These hybrids should be able to synergistically overcome P-gp mediated multidrug resistance (MDR) in cancer cells. It was reported that the efflux activity of P-gp could be modulated by CA XII, as the pH reduction caused by CA XII inhibition produces a significant decrease in P-gp ATPase activity. The new compounds reported here feature both P-gp and CA XII binding moieties. These hybrids contain a N,N-bis(alkanol)amine diester scaffold found in P-glycoprotein ligands and a coumarin or benzene sulfonamide moiety to target CA XII. Many compounds displayed a dual activity against P-gp and CA XII being active in the Rhd 123 uptake test on K562/DOX cells and in the hCA XII inhibition test. On LoVo/DOX cells, that overexpress both P-gp and CA XII, some coumarin derivatives showed a high MDR reversal effect in Rhd 123 uptake and doxorubicin cytotoxicity enhancement tests. In particular, compounds 7 and 8 showed higher activity than verapamil and were more potent on LoVo/DOX than on K562/DOX cells overexpressing only P-gp. They can be considered as valuable candidates for selective P-gp/CA XII inhibition in MDR cancer cells.

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Development of a Novel Quinoline Derivative as a P-Glycoprotein Inhibitor to Reverse Multidrug Resistance in Cancer Cells

Biology ◽

10.3390/biology8040075 ◽

2019 ◽

Vol 8 (4) ◽

pp. 75 ◽

Cited By ~ 1

Author(s):

Yuanyuan Zhou ◽

Po-yee Chung ◽

Jessica Yuen-wuen Ma ◽

Alfred King-yin Lam ◽

Simon Law ◽

...

Keyword(s):

Multidrug Resistance ◽

Cancer Cells ◽

Cell Lines ◽

Anticancer Agents ◽

Underlying Mechanism ◽

Quinoline Derivative ◽

Parental Cancer ◽

Reversal Effect ◽

P Glycoprotein ◽

Mdr Reversal

Multidrug resistance (MDR) is one of conventional cancer chemotherapy’s limitations. Our group previously synthesized a series of quinoline-based compounds in an attempt to identify novel anticancer agents. With a molecular docking analysis, the novel compound 160a was predicted to target p-glycoprotein, an MDR candidate. The purpose of this study is to evaluate 160a’s MDR reversal effect and investigate the underlying mechanism at the molecular level. To investigate 160a’s inhibitory effect, we used a series of parental cancer cell lines (A549, LCC6, KYSE150, and MCF-7), the corresponding doxorubicin-resistant cell lines, an MTS cytotoxicity assay, an intracellular doxorubicin accumulation test, and multidrug resistance assays. The Compusyn program confirmed, with a combination index (CI) value greater than 1, that 160a combined with doxorubicin exerts a synergistic effect. Intracellular doxorubicin accumulation and transported calcein acetoxymethyl (AM) (a substrate for p-glycoprotein) were both increased when cancer cells with MDR were treated with compound 160a. We also showed that compound 160a’s MDR reversal effect can persist for at least 1 h. Taken together, these results suggest that the quinoline compound 160a possesses high potential to reverse MDR by inhibiting p-glycoprotein-mediated drug efflux in cancer cells with MDR.

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DJ-1 is involved in the multidrug resistance of SGC7901 gastric cancer cells through PTEN/PI3K/Akt/Nrf2 pathway

Acta Biochimica et Biophysica Sinica ◽

10.1093/abbs/gmaa110 ◽

2020 ◽

Vol 52 (11) ◽

pp. 1202-1214

Author(s):

Lejia Qiu ◽

Zhaoxia Ma ◽

Xiaoran Li ◽

Yizhang Deng ◽

Guangling Duan ◽

...

Keyword(s):

Gastric Cancer ◽

Multidrug Resistance ◽

Cancer Cells ◽

Gastric Cancer Cells ◽

Glycoprotein P ◽

Nrf2 Pathway ◽

P Glycoprotein ◽

New Findings ◽

Nrf2 Signaling Pathway ◽

Common Malignancy

Abstract Gastric cancer is a common malignancy worldwide. The occurrence of multidrug resistance (MDR) is the major obstacle for effective gastric cancer chemotherapy. In this study, the in-depth molecular mechanism of the DJ-1-induced MDR in SGC7901 gastric cancer cells was investigated. The results showed that DJ-1 expression level was higher in MDR variant SGC7901/VCR cells than that in its parental SGC7901 cells. Moreover, DJ-1 overexpression conferred the MDR phenotype to SGC7901 cells, while DJ-1 knockdown in SGC7901/VCR cells induced re-sensitization to adriamycin, vincristine, cisplatin, and 5-fluorouracil. These results suggested that DJ-1 mediated the development of MDR in SGC7901 gastric cancer cells. Importantly, further data revealed that the activation of PI3k/Akt and Nrf2 signaling pathway were required for the DJ-1-induced MDR phenotype in SGC7901 gastric cancer cells. Meanwhile, we found that PI3k/Akt pathway was activated probably through DJ-1 directly binding to and negatively regulating PTEN, consequently resulting in Nrf2 phosphorylation and activation, and thereby inducing Nrf2-dependent P-glycoprotein (P-gp) and Bcl-2 expressions in the DJ-1-mediated MDR of SGC7901 gastric cancer cells. Overall, these results revealed that activating PTEN/PI3K/Akt/Nrf2 pathway and subsequently upregulating P-gp and Bcl-2 expression could be a critical mechanism by which DJ-1 mediates the development of MDR in SGC7901 gastric cancer cells. The new findings may be helpful for understanding the mechanisms of MDR in gastric cancer cells, prompting its further investigation as a molecular target to overcome MDR.

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Cross-linking of S-nitrosothiolated AIEgen inside cancer cells to monitor NO release and reverse chemo-resistance

Chemical Communications ◽

10.1039/d1cc05504f ◽

2021 ◽

Author(s):

Wen WU ◽

Fan Ying ◽

Luo Ting Rong ◽

Yuchen Hu ◽

Qingyu Zhang ◽

...

Keyword(s):

Nitric Oxide ◽

Multidrug Resistance ◽

Cancer Cells ◽

Cross Linking ◽

Glycoprotein P ◽

P Glycoprotein ◽

No Release

Nitric oxide (NO)-releasing platforms have been demonstrated as promising approaches for the reversal of multidrug resistance (MDR) in cancer cells due to the suppression of P-glycoprotein (P-gp). However, the non-specific...

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Screening dietary flavonoids for the reversal of P-glycoprotein-mediated multidrug resistance in cancer

Molecular BioSystems ◽

10.1039/c6mb00187d ◽

2016 ◽

Vol 12 (8) ◽

pp. 2458-2470 ◽

Cited By ~ 33

Author(s):

S. Mohana ◽

M. Ganesan ◽

B. Agilan ◽

R. Karthikeyan ◽

G. Srithar ◽

...

Keyword(s):

Multidrug Resistance ◽

Cancer Cells ◽

Therapeutic Target ◽

Glycoprotein P ◽

P Glycoprotein ◽

Dietary Flavonoids

P-Glycoprotein (P-gp) serves as a therapeutic target for the development of inhibitors to overcome multidrug resistance in cancer cells.

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Unsymmetric dihydropyridines bearing 2-pyridyl methyl carboxylate as modulators of P-glycoprotein; synthesis and biological evaluation in resistant and non-resistant cancer cells

Canadian Journal of Chemistry ◽

10.1139/cjc-2018-0351 ◽

2019 ◽

Vol 97 (8) ◽

pp. 603-614

Author(s):

Maryam Nejati ◽

Hossein Sadeghpour ◽

Sara Ranjbar ◽

Katayoun Javidnia ◽

Najmeh Edraki ◽

...

Keyword(s):

Cancer Cells ◽

Human Cancer ◽

Binding Mode ◽

Biological Evaluation ◽

Multi Drug Resistance ◽

Glycoprotein P ◽

Glycoprotein Synthesis ◽

Human Cancer Cells ◽

P Glycoprotein ◽

Mdr Reversal

Multi-drug resistance (MDR) in cancer cells is often associated with overexpression of P-glycoprotein (P-gp or ABCB1 or MDR1); therefore, modulators of this transporter might be helpful in overcoming MDR. In this study, 16 novel unsymmetrical dihydropyridine (DHP) derivatives bearing 2-pyridyl methyl carboxylate at C3 and a nitroimidazole or nitrophenyl ring at C4 positions of the DHP ring were synthesized. Their cytotoxicity was tested against four human cancer cells by MTT assay. The reversal capacity of MDR was examined in P-gp overexpressing cells (MES-SA/DX5) by measuring the alteration of doxorubicin’s IC50 and performing flow cytometric determination of intracellular rhodamine 123 accumulation. The calcium channel blocking (CCB) activity, as a side effect of DHPs, was tested on the ileum of a guinea pig. Molecular docking was performed to explain the binding mode of compounds. Two derivatives, 4a and 4c, containing 4-nitrophenyl at C4 and possessing methyl (4a) and iso-propyl (4c) carboxylates at the C5 position of DHP core demonstrated superior cytotoxic and MDR reversal activities and lower CCB effect. Docking analysis confirmed the importance of the 4-nitrophenyl ring for P-gp inhibitory activity. Some of the synthesized DHP derivatives with considerable MDR reversal capacity could be promising compounds for further discovery of useful agents for management of drug resistant cancer.

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Reversal of P-glycoprotein-mediated multidrug resistance by novel curcumin analogues in paclitaxel-resistant human breast cancer cells

Biochemistry and Cell Biology ◽

10.1139/bcb-2019-0377 ◽

2020 ◽

Vol 98 (4) ◽

pp. 484-491 ◽

Cited By ~ 7

Author(s):

Lei Gao ◽

Peiran Zhao ◽

Yang Li ◽

Dawei Yang ◽

Ping Hu ◽

...

Keyword(s):

Breast Cancer ◽

Multidrug Resistance ◽

Cancer Cells ◽

Cancer Cell Line ◽

Positive Control ◽

Promising Candidate ◽

Glycoprotein P ◽

Compound C ◽

P Glycoprotein ◽

Low Toxicity

Multidrug resistance (MDR) is a major obstacle for successful cancer chemotherapy, and the main cause of MDR has been attributed to overexpression of P-glycoprotein (P-gp). In this present study, four P-gp modulators (E,E)-4,6-bis(styryl)-2-(substituted amino)-pyrimidines were evaluated for their activity in a breast cancer cell line overexpressing P-gp (LCC6MDR). The four modulators displayed significantly better P-gp modulating activity compared with the positive control verapamil (RF = 5.4), with a relative fold (RF) increase in activity ranging from 33.3 to 86.0. In contrast to compounds a and c that exhibited lower cytotoxicity, compounds b and d were nontoxic towards both cancer cells and normal cells, with IC50 values greater than 100 μmol/L. The qRT-PCR results demonstrated that after exposure to 2 μmol/L of compounds a, b, c, and d, the mRNA expression level of MDR1 in LCC6MDR cells decreased to 45%, 50%, 38%, and 51%, respectively. However, the Western-blot results indicated that compound c could reverse P-gp mediated MDR, but not via decreases in protein expression. DOX and Rh123 accumulation and efflux results further confirmed that the reversal of MDR activity happens via inhibition of P-gp efflux and increases in intracellular drug accumulation. These results demonstrated that compound c has low toxicity and is an efficient P-gp modulator, highlighting its potential as a promising candidate for P-gp-mediated reversal of MDR.

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Reversal of P-glycoprotein (P-gp) mediated multidrug resistance in colon cancer cells by cryptotanshinone and dihydrotanshinone of Salvia miltiorrhiza

Phytomedicine ◽

10.1016/j.phymed.2014.06.013 ◽

2014 ◽

Vol 21 (11) ◽

pp. 1264-1272 ◽

Cited By ~ 52

Author(s):

Tao Hu ◽

Kenneth K.W. To ◽

Lin Wang ◽

Lin Zhang ◽

Lan Lu ◽

...

Keyword(s):

Colon Cancer ◽

Multidrug Resistance ◽

Cancer Cells ◽

Salvia Miltiorrhiza ◽

Colon Cancer Cells ◽

Glycoprotein P ◽

P Glycoprotein

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Multiple Molecular Mechanisms to Overcome Multidrug Resistance in Cancer by Natural Secondary Metabolites

Frontiers in Pharmacology ◽

10.3389/fphar.2021.658513 ◽

2021 ◽

Vol 12 ◽

Author(s):

Mahmoud Zaki El-Readi ◽

Ahmed M. Al-Abd ◽

Mohammad A. Althubiti ◽

Riyad A. Almaimani ◽

Hiba Saeed Al-Amoodi ◽

...

Keyword(s):

Multidrug Resistance ◽

Secondary Metabolites ◽

Cancer Cells ◽

Molecular Mechanisms ◽

Plant Secondary Metabolites ◽

Cell Growth Inhibition ◽

Glycoprotein P ◽

P Glycoprotein ◽

Drug Concentrations ◽

Pharmaceutical Agents

Plant secondary metabolites (SMs) common natural occurrences and the significantly lower toxicities of many SM have led to the approaching development and use of these compounds as effective pharmaceutical agents; especially in cancer therapy. A combination of two or three of plant secondary metabolites together or of one SM with specific anticancer drugs, may synergistically decrease the doses needed, widen the chemotherapeutic window, mediate more effective cell growth inhibition, and avoid the side effects of high drug concentrations. In mixtures they can exert additive or even synergistic activities. Many SM can effectively increase the sensitivity of cancer cells to chemotherapy. In phytotherapy, secondary metabolites (SM) of medicinal plants can interact with single or multiple targets. The multi-molecular mechanisms of plant secondary metabolites to overcome multidrug resistance (MDR) are highlighted in this review. These mechanisms include interaction with membrane proteins such as P-glycoprotein (P-gp/MDR1); an ATP-binding cassette (ABC) transporter, nucleic acids (DNA, RNA), and induction of apoptosis. P-gp plays an important role in the development of MDR in cancer cells and is involved in potential chemotherapy failure. Therefore, the ingestion of dietary supplements, food or beverages containing secondary metabolites e.g., polyphenols or terpenoids may alter the bioavailability, therapeutic efficacy and safety of the drugs that are P-gp substrates.

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Reversal of P-glycoprotein-mediated multidrug resistance and pharmacokinetics study in rats by WYX-5

Canadian Journal of Physiology and Pharmacology ◽

10.1139/cjpp-2016-0518 ◽

2017 ◽

Vol 95 (5) ◽

pp. 580-585 ◽

Cited By ~ 2

Author(s):

Yuzhu Wang ◽

Jian Cui ◽

Yuxuan Dai ◽

Yuxiang Wu ◽

Wenlong Huang ◽

...

Keyword(s):

Multidrug Resistance ◽

Therapeutic Index ◽

Glycoprotein P ◽

Reversal Effect ◽

P Glycoprotein ◽

Relative Safety ◽

Reversal Mechanism ◽

Low Cytotoxicity

Multidrug resistance (MDR) is one of the major obstacles confronted in cancer chemotherapy; this obstacle is mainly due to the overexpression of P-glycoprotein (P-gp). Co-administration of anticancer drugs and P-gp inhibitors is a promising approach to overcome MDR. WYX-5, a novel P-gp inhibitor, shows a notable reversal effect with low cytotoxicity in vitro. In this paper, the reversal mechanism and safety of the MDR modulator WYX-5 were explored in vitro, and evaluated for its pharmacokinetics and effects on adriamycin (ADM) metabolism in vivo. The results suggest that WYX-5 is a potent P-gp inhibitor with EC50 in nanomole range (EC50 = 204.3 ± 20.2 nmol·L−1), relative safety (therapeutic index = 446.4), which performs as a substrate of P-gp and retrains its function. Further, WYX-5 (5 mg·kg−1) had relatively ideal pharmacokinetic properties (T1/2 = 6.448 h, F = 96.05%) without interactions with ADM metabolism in vivo. In conclusion, WYX-5 may be a promising candidate for MDR cancer combined-chemotherapy research.

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