Potential drug candidates as P-glycoprotein inhibitors to reverse multidrug resistance in cancer: an
            <i>in silico</i>
            drug discovery study

Abdeljawaad, Khlood A. A.; Jaragh-Alhadad, Laila A.; Oraby, Hesham F.; Atia, Mohamed A. M.; Alzahrani, Othman R.; Mekhemer, Gamal A. H.; Moustafa, Mahmoud; Shawky, Ahmed M.; Sidhom, Peter A.; Abdelrahman, Alaa H. M.

doi:10.1080/07391102.2023.2176360

Cited by 6 publications

(6 citation statements)

References 60 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This gene play an important role in the bioavailability of toxic substances and metabolites and prevents their intracellular accumulation. The ABCB1 3435 C > T polymorphism (rs1045642) decreases the enzymatic activity of P-gp and reduces the number of carriers, leading to intracellular accumulation of drugs with associated toxic effects 30 . ABCB1 corresponds to a wide range of drug substrate actions that affects the toxic response of several antineoplastic drugs, such as carboplatin 31 , cisplatin 32 , MTX 33 , uorouracil 34 , adriamycin 35 , etc.…”

Section: Discussionmentioning

confidence: 99%

Effects of gene polymorphisms on delayed MTX clearance, toxicity, and metabolomic changes after HD-MTX treatment in children with acute lymphoblastic leukemia

Zhou,

He,

Ding

et al. 2023

Eur J Pediatr

View full text Add to dashboard Cite

To assess the role of methotrexate-related gene polymorphisms in children with acute lymphoblastic leukemia (ALL) during high-dose methotrexate (HD-MTX) therapy and to explore their effects on serum metabolites before and after HD-MTX treatment. MethodsThe MTHFR 677C > T, MTHFR 1298A > C, ABCB1 3435C > T, and GSTP1 313A > G genotypes of 189 children with ALL who received chemotherapy with the CCCG-ALL-2020 regimen from January 2020 to April 2023 were analyzed, and toxic effects were reported according to the Common Terminology Criteria for Adverse Events (CTCAE, version 5.0). Fasting peripheral blood serum samples were collected from 27 children before and after HD-MTX treatment, and plasma metabolites were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS). ResultsThe results of univariate and multivariate analyses showed that MTHFR 677C > T and ABCB1 3435 C T gene polymorphisms were associated with the delayed MTX clearance (P < 0.05) and lower platelet count after treatment in children with MTHFR 677 mutation compared with wild-type ones (P < 0.05), and pure mutations in ABCB1 3435 were associated with higher serum creatinine levels (P < 0.05). No signi cant association was identi ed between MTHFR 677C > T, MTHFR 1298A > C, ABCB1 3435 C > T, and GSTP1 313A > G genes and hepatotoxicity or nephrotoxicity (P > 0.05). However, the serum metabolomic analysis indicated that the presence of the MTHFR 677C > T gene polymorphism could potentially contribute to delayed MTX clearance by in uencing L-phenylalanine metabolism, leading to the occurrence of related toxic side effects. ConclusionMTHFR 677C > T and ABCB1 3435 C > T predicted the risk of delayed MTX clearance during HD-MTX treatment in children with ALL. Serum L-phenylalanine levels were signi cantly elevated after HD-MTX treatment in children with the MTHFR 677C > T mutation gene. 1.Introduction Acute lymphoblastic leukemia (ALL) is one of the most common childhood malignancies, characterized by the abnormal proliferation of lymphoblasts. Over the years, advancements in combination chemotherapy regimens have signi cantly improved the prognosis for children with ALL. The survival

show abstract

Section: Discussionmentioning

confidence: 99%

Effects of gene polymorphisms on delayed MTX clearance, toxicity, and metabolomic changes after HD-MTX treatment in children with acute lymphoblastic leukemia

Zhou,

He,

Ding

et al. 2023

Eur J Pediatr

View full text Add to dashboard Cite

show abstract

Section: Discussionmentioning

confidence: 99%

Effects of gene polymorphisms on delayed MTX clearance, toxicity, and metabolomic changes after HD-MTX treatment in children with acute lymphoblastic leukemia

Zhou

Ding

et al. 2023

Preprint

View full text Add to dashboard Cite

Objective To assess the role of methotrexate-related gene polymorphisms in children with acute lymphoblastic leukemia (ALL) during high-dose methotrexate (HD-MTX) therapy and to explore their effects on serum metabolites before and after HD-MTX treatment. Methods The MTHFR 677C > T, MTHFR 1298A > C, ABCB1 3435C > T, and GSTP1 313A > G genotypes of 189 children with ALL who received chemotherapy with the CCCG-ALL-2020 regimen from January 2020 to April 2023 were analyzed, and toxic effects were reported according to the Common Terminology Criteria for Adverse Events (CTCAE, version 5.0). Fasting peripheral blood serum samples were collected from 27 children before and after HD-MTX treatment, and plasma metabolites were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS). Results The results of univariate and multivariate analyses showed that MTHFR 677C > T and ABCB1 3435 C༞T gene polymorphisms were associated with the delayed MTX clearance (P < 0.05) and lower platelet count after treatment in children with MTHFR 677 mutation compared with wild-type ones (P < 0.05), and pure mutations in ABCB1 3435 were associated with higher serum creatinine levels (P < 0.05). No significant association was identified between MTHFR 677C > T, MTHFR 1298A > C, ABCB1 3435 C > T, and GSTP1 313A > G genes and hepatotoxicity or nephrotoxicity (P > 0.05). However, the serum metabolomic analysis indicated that the presence of the MTHFR 677C > T gene polymorphism could potentially contribute to delayed MTX clearance by influencing L-phenylalanine metabolism, leading to the occurrence of related toxic side effects. Conclusion MTHFR 677C > T and ABCB1 3435 C > T predicted the risk of delayed MTX clearance during HD-MTX treatment in children with ALL. Serum L-phenylalanine levels were significantly elevated after HD-MTX treatment in children with the MTHFR 677C > T mutation gene.

show abstract

“…P-glycoprotein (ABCB1, MDR1) is the most understood member of the MDR/TAP family, which also includes the homologs ABCB1-11, while the breast cancer resistance protein (BCRP, ABCG2) is the best-understood member of the ABCG family of transporters [ 63 , 64 , 65 ]. Different in gene location, amino acid sequence, structure, and substrate selectivity, these resistance-conferring proteins are all a part of the ABC superfamily [ 66 , 67 , 68 ]. Many of these have been defined in humans and are naturally expressed in a wide variety of healthy tissues as well as neoplasms [ 69 ].…”

Section: Mechanisms Of Cancer Chemoresistancementioning

confidence: 99%

Insights on the Role of Polyphenols in Combating Cancer Drug Resistance

Farhan

2023

Biomedicines

View full text Add to dashboard Cite

Chemotherapy resistance is still a serious problem in the treatment of most cancers. Many cellular and molecular mechanisms contribute to both inherent and acquired drug resistance. They include the use of unaffected growth-signaling pathways, changes in the tumor microenvironment, and the active transport of medicines out of the cell. The antioxidant capacity of polyphenols and their potential to inhibit the activation of procarcinogens, cancer cell proliferation, metastasis, and angiogenesis, as well as to promote the inhibition or downregulation of active drug efflux transporters, have been linked to a reduced risk of cancer in epidemiological studies. Polyphenols also have the ability to alter immunological responses and inflammatory cascades, as well as trigger apoptosis in cancer cells. The discovery of the relationship between abnormal growth signaling and metabolic dysfunction in cancer cells highlights the importance of further investigating the effects of dietary polyphenols, including their ability to boost the efficacy of chemotherapy and avoid multidrug resistance (MDR). Here, it is summarized what is known regarding the effectiveness of natural polyphenolic compounds in counteracting the resistance that might develop to cancer drugs as a result of a variety of different mechanisms.

show abstract

Potential drug candidates as P-glycoprotein inhibitors to reverse multidrug resistance in cancer: an in silico drug discovery study

Cited by 6 publications

References 60 publications

Effects of gene polymorphisms on delayed MTX clearance, toxicity, and metabolomic changes after HD-MTX treatment in children with acute lymphoblastic leukemia

Effects of gene polymorphisms on delayed MTX clearance, toxicity, and metabolomic changes after HD-MTX treatment in children with acute lymphoblastic leukemia

Effects of gene polymorphisms on delayed MTX clearance, toxicity, and metabolomic changes after HD-MTX treatment in children with acute lymphoblastic leukemia

Insights on the Role of Polyphenols in Combating Cancer Drug Resistance

Contact Info

Product

Resources

About