Overcoming Cancer Multi-drug Resistance (MDR): Reasons, mechanisms, nanotherapeutic solutions, and challenges

Duan, Chunyan; Yu, Mingjia; Xu, Jie; Li, Boyi; Ying, Zhao; Kankala, Ranjith Kumar

doi:10.1016/j.biopha.2023.114643

Cited by 59 publications

(38 citation statements)

References 193 publications

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“…Fourth-generation ABC efflux pump inhibitors are natural compounds and flavonoids that demonstrated therapeutic efficacy with no toxicity [280]. However, in spite potent inhibition, therapeutic success was limited due to low solubility and bioavailability [280,281]. Recently, lipid-based nanocarriers and biomimetic magnetic nanoparticles functionalized fourth-gen ABC efflux pump inhibitors have shown pharmacological promise against drug resistant cancers [281,282].…”

Section: Targeting Tumor Bioenergetics and Resistant Niches Through N...mentioning

confidence: 99%

“…However, in spite potent inhibition, therapeutic success was limited due to low solubility and bioavailability [280,281]. Recently, lipid-based nanocarriers and biomimetic magnetic nanoparticles functionalized fourth-gen ABC efflux pump inhibitors have shown pharmacological promise against drug resistant cancers [281,282]. Small interfering RNAs (siRNA) as inhibition for ABC drug efflux pumps were also tested in patients [283,284].…”

Section: Targeting Tumor Bioenergetics and Resistant Niches Through N...mentioning

confidence: 99%

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Cancer Bioenergetics and Tumor Microenvironments—Enhancing Chemotherapeutics and Targeting Resistant Niches through Nanosystems

Farhana

Alsrhani

Khan

et al. 2023

Cancers

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Cancer is an impending bottleneck in the advanced scientific workflow to achieve diagnostic, prognostic, and therapeutic success. Most cancers are refractory to conventional diagnostic and chemotherapeutics due to their limited targetability, specificity, solubility, and side effects. The inherent ability of each cancer to evolve through various genetic and epigenetic transformations and metabolic reprogramming underlies therapeutic limitations. Though tumor microenvironments (TMEs) are quite well understood in some cancers, each microenvironment differs from the other in internal perturbations and metabolic skew thereby impeding the development of appropriate diagnostics, drugs, vaccines, and therapies. Cancer associated bioenergetics modulations regulate TME, angiogenesis, immune evasion, generation of resistant niches and tumor progression, and a thorough understanding is crucial to the development of metabolic therapies. However, this remains a missing element in cancer theranostics, necessitating the development of modalities that can be adapted for targetability, diagnostics and therapeutics. In this challenging scenario, nanomaterials are modular platforms for understanding TME and achieving successful theranostics. Several nanoscale particles have been successfully researched in animal models, quite a few have reached clinical trials, and some have achieved clinical success. Nanoparticles exhibit an intrinsic capability to interact with diverse biomolecules and modulate their functions. Furthermore, nanoparticles can be functionalized with receptors, modulators, and drugs to facilitate specific targeting with reduced toxicity. This review discusses the current understanding of different theranostic nanosystems, their synthesis, functionalization, and targetability for therapeutic modulation of bioenergetics, and metabolic reprogramming of the cancer microenvironment. We highlight the potential of nanosystems for enhanced chemotherapeutic success emphasizing the questions that remain unanswered.

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Section: Targeting Tumor Bioenergetics and Resistant Niches Through N...mentioning

confidence: 99%

Section: Targeting Tumor Bioenergetics and Resistant Niches Through N...mentioning

confidence: 99%

Cancer Bioenergetics and Tumor Microenvironments—Enhancing Chemotherapeutics and Targeting Resistant Niches through Nanosystems

Farhana

Alsrhani

Khan

et al. 2023

Cancers

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“…Also, many efflux inhibitors can cause dose-dependent side effects due to inhibiting these transporters in healthy tissues. A small molecule that can bypass these efflux transporters may have an improved therapeutic window and safety profile. , Therefore, it is crucial to determine whether ES–Cu can be pumped outside of cells by efflux transporters and develop administration strategies that can effectively inhibit or bypass these transporters to increase intracellular drug concentrations.…”

Section: Introductionmentioning

confidence: 99%

Elesclomol-Copper Nanoparticles Overcome Multidrug Resistance in Cancer Cells

Wang,

Huang,

Wibowo

et al. 2024

ACS Appl. Mater. Interfaces

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Elesclomol (ES), a copper-binding ionophore, forms an ES−Cu complex with copper ions (Cu(II)). ES−Cu has been proven to induce mitochondrial oxidative stress and copper-dependent cell death (cuprotosis). However, ES−Cu is poorly water-soluble, and its delivery to various cancer cells is a challenge. Herein, we designed a D-α-tocopherol polyethylene glycol 1000 succinate/chondroitin sulfate-cholic acid (TPGS/CS−CA)-based micellar nanoparticle for delivering the ES−Cu complex to various cancer cell lines to demonstrate its efficacy as an anticancer agent. The ES−Cu nanoparticles exerted high encapsulation efficiency and excellent serum stability. The anticancer efficacy of ES−Cu nanoparticles was evaluated in various drug-sensitive cell lines (DU145, PC3, and A549) and drug-resistant cell lines (DU145TXR, PC3TXR, and A549TXR). The results showed that ES−Cu nanoparticles exerted potent anticancer activities in both drug-sensitive and drugresistant cell lines. The Western blotting, reverse transcription quantitative polymerase chain reaction (RT-qPCR), and molecular docking results suggested that ES−Cu is not a substrate for P glycoprotein (P-gp), which is an efflux transporter potentially causing multidrug resistance (MDR) in cancer cells. ES−Cu nanoparticles could bypass P-gp without compromising their activity, indicating that they may overcome MDR in cancer cells and provide a novel therapeutic strategy. Additionally, the extracellular matrix of ES−Cu nanoparticles-pretreated drug-resistant cells could polarize Raw 264.7 macrophages into the M1 phenotype. Therefore, our TPGS/CS−CA-based ES−Cu nanoparticles provide an effective method of delivering the ES−Cu complex, a promising strategy to overcome MDR in cancer therapy with potential immune response stimulation.

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“…10 However, most available medications lack specicity, which brings up problems like the well-documented side effects of cancer treatment 11 and the much more widespread phenomenon of multi-drug resistance. 12 DNA topoisomerases are enzymes that play a crucial role in regulating DNA twists and folds. 13 Topoisomerases also play a vital role in preserving the structural integrity and stability of DNA, 14 which is essential for many complex biological processes like transcription, replication, and recombination 15 but can impede these activities and slow cell growth.…”

Section: Introductionmentioning

confidence: 99%

Novel 2-substituted-quinoxaline analogs with potential antiproliferative activity against breast cancer: insights into cell cycle arrest, topoisomerase II, and EGFR activity

Salem,

Abu El-ata,

Elsayed

et al. 2023

RSC Adv.

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Overcoming Cancer Multi-drug Resistance (MDR): Reasons, mechanisms, nanotherapeutic solutions, and challenges

Cited by 59 publications

References 193 publications

Cancer Bioenergetics and Tumor Microenvironments—Enhancing Chemotherapeutics and Targeting Resistant Niches through Nanosystems

Cancer Bioenergetics and Tumor Microenvironments—Enhancing Chemotherapeutics and Targeting Resistant Niches through Nanosystems

Elesclomol-Copper Nanoparticles Overcome Multidrug Resistance in Cancer Cells

Novel 2-substituted-quinoxaline analogs with potential antiproliferative activity against breast cancer: insights into cell cycle arrest, topoisomerase II, and EGFR activity

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