Advances in understanding the role of P-gp in doxorubicin resistance: Molecular pathways, therapeutic strategies, and prospects

Mirzaei, Sepideh; Gholami, Milad; Hashemi, Farid; Zabolian, Amirhossein; Farahani, Mahdi Vasheghani; Hushmandi, Kiavash; Zarrabi, Ali; Goldman, Aaron; Ashrafizadeh, Milad; Orive, Gorka

doi:10.1016/j.drudis.2021.09.020

Cited by 97 publications

(64 citation statements)

References 271 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The obtained data demonstrated the low susceptibility of all analyzed compounds to P-gp transport, among which p -substituted anilides ( 8 , 9 ) and tryptamide 12 were predicted as non-substrates of P-gp by all the chemoinformatics tools used ( Figure 3 C, left heatmap). The computed results are in line with published data: doxorubicin is a known substrate of P-gp [ 45 ], whereas SM was found to exhibit similar cytotoxicity against cervical carcinoma cells independently on their P-gp expression status [ 29 , 31 ]. Moreover, in silico analysis also revealed that the evaluated molecules can inhibit the efflux activity of P-gp ( Figure 3 C, right heatmap).…”

Section: Resultssupporting

confidence: 88%

Novel Soloxolone Amides as Potent Anti-Glioblastoma Candidates: Design, Synthesis, In Silico Analysis and Biological Activities In Vitro and In Vivo

et al. 2022

View full text Add to dashboard Cite

The modification of natural or semisynthetic triterpenoids with amines can be explored as a promising strategy for improving their pharmacological properties. Here, we report the design and synthesis of 11 novel amide derivatives of soloxolone methyl (SM), a cyano enone-bearing derivative of 18βH-glycyrrhetinic acid. Analysis of their bioactivities in vitro and in silico revealed their high toxicity against a panel of tumor cells (average IC50(24 h) = 3.7 µM) and showed that the formation of amide moieties at the C-30 position of soloxolone did not enhance the cytotoxicity of derivatives toward tumor cells compared to SM, though it can impart an ability to pass across the blood–brain barrier. Further HPLC–MS/MS and mechanistic studies verified significant brain accumulation of hit compound 12 (soloxolone tryptamide) in a murine model and showed its high anti-glioblastoma potential. It was found that 12 induced ROS-dependent and autophagy-independent death of U87 and U118 glioblastoma cells via mitochondrial apoptosis and effectively blocked their clonogenicity, motility and capacity to form vessel-like structures. Further in vivo study demonstrated that intraperitoneal injection of 12 at a dosage of 20 mg/kg effectively inhibited the growth of U87 glioblastoma in a mouse xenograft model, reducing the proliferative potential of the tumor and leading to a depletion of collagen content and normalization of blood vessels in tumor tissue. The obtained results clearly demonstrate that 12 can be considered as a promising leading compound for drug development in glioblastoma treatment.

show abstract

Section: Resultssupporting

confidence: 88%

Novel Soloxolone Amides as Potent Anti-Glioblastoma Candidates: Design, Synthesis, In Silico Analysis and Biological Activities In Vitro and In Vivo

et al. 2022

View full text Add to dashboard Cite

show abstract

“…Following hTERT down-regulation by siRNA, expressions of Bcl-2 and COX-2, as tumor-promoting factors undergo inhibition that is of importance for inducing apoptosis in PC cells [189], and enhancing their sensitivity to chemotherapy. Now, it is obvious that when cancer cells demonstrate malignant behavior in terms of proliferation and migration, they can obtain chemoresistance [190][191][192][193][194][195][196]. Therefore, in order to provide effective cancer chemotherapy, it is vital to suppress the various pathways that lead to cancer migration and growth [193,197].…”

Section: Therapy Response and Synergistic Therapymentioning

confidence: 99%

“…Now, it is obvious that when cancer cells demonstrate malignant behavior in terms of proliferation and migration, they can obtain chemoresistance [ 190 , 191 , 192 , 193 , 194 , 195 , 196 ]. Therefore, in order to provide effective cancer chemotherapy, it is vital to suppress the various pathways that lead to cancer migration and growth [ 193 , 197 ].…”

Section: Sirna and Pancreatic Cancer Therapymentioning

confidence: 99%

Pre-Clinical and Clinical Applications of Small Interfering RNAs (siRNA) and Co-Delivery Systems for Pancreatic Cancer Therapy

Mirzaei

Gholami

Ang

et al. 2021

Cells

Self Cite

View full text Add to dashboard Cite

Pancreatic cancer (PC) is one of the leading causes of death and is the fourth most malignant tumor in men. The epigenetic and genetic alterations appear to be responsible for development of PC. Small interfering RNA (siRNA) is a powerful genetic tool that can bind to its target and reduces expression level of a specific gene. The various critical genes involved in PC progression can be effectively targeted using diverse siRNAs. Moreover, siRNAs can enhance efficacy of chemotherapy and radiotherapy in inhibiting PC progression. However, siRNAs suffer from different off target effects and their degradation by enzymes in serum can diminish their potential in gene silencing. Loading siRNAs on nanoparticles can effectively protect them against degradation and can inhibit off target actions by facilitating targeted delivery. This leads to enhanced efficacy of siRNAs in PC therapy. Moreover, different kinds of nanoparticles such as polymeric nanoparticles, lipid nanoparticles and metal nanostructures have been applied for optimal delivery of siRNAs that are discussed in this article. This review also reveals that how naked siRNAs and their delivery systems can be exploited in treatment of PC and as siRNAs are currently being applied in clinical trials, significant progress can be made by translating the current findings into the clinical settings.

show abstract

“…However, a problem with targeted drug therapy is the emergence of cancer drug resistance [2], as with chemotherapy [3,4]. Many studies have investigated the mechanisms of resistance to chemotherapy and their solutions [5][6][7][8][9][10][11][12][13][14]. The mechanisms of how cancer cells acquire targeted drug resistance are not clarified.…”

Section: Introductionmentioning

confidence: 99%

Predicting Anticancer Drug Resistance Mediated by Mutations

et al. 2022

View full text Add to dashboard Cite

Cancer drug resistance presents a challenge for precision medicine. Drug-resistant mutations are always emerging. In this study, we explored the relationship between drug-resistant mutations and drug resistance from the perspective of protein structure. By combining data from previously identified drug-resistant mutations and information of protein structure and function, we used machine learning-based methods to build models to predict cancer drug resistance mutations. The performance of our combined model achieved an accuracy of 86%, a Matthews correlation coefficient score of 0.57, and an F1 score of 0.66. We have constructed a fast, reliable method that predicts and investigates cancer drug resistance in a protein structure. Nonetheless, more information is needed concerning drug resistance and, in particular, clarification is needed about the relationships between the drug and the drug resistance mutations in proteins. Highly accurate predictions regarding drug resistance mutations can be helpful for developing new strategies with personalized cancer treatments. Our novel concept, which combines protein structure information, has the potential to elucidate physiological mechanisms of cancer drug resistance.

show abstract

Advances in understanding the role of P-gp in doxorubicin resistance: Molecular pathways, therapeutic strategies, and prospects

Cited by 97 publications

References 271 publications

Novel Soloxolone Amides as Potent Anti-Glioblastoma Candidates: Design, Synthesis, In Silico Analysis and Biological Activities In Vitro and In Vivo

Novel Soloxolone Amides as Potent Anti-Glioblastoma Candidates: Design, Synthesis, In Silico Analysis and Biological Activities In Vitro and In Vivo

Pre-Clinical and Clinical Applications of Small Interfering RNAs (siRNA) and Co-Delivery Systems for Pancreatic Cancer Therapy

Predicting Anticancer Drug Resistance Mediated by Mutations

Contact Info

Product

Resources

About