MDR in cancer: Addressing the underlying cellular alterations with the use of nanocarriers

Singh, Manu Smriti; Tammam, Salma N.; Boushehri, Maryam A. Shetab; Lamprecht, Alf

doi:10.1016/j.phrs.2017.07.023

Cited by 53 publications

(37 citation statements)

References 320 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…16 Nanoparticles have been suggested to act as "stealth" carriers for cargos to evade discharge by Pgp-efflux pumps by impeding direct interaction of cargos with membrane and by being internalized through endocytosis in nanoparticle-associated form, rather than through diffusion across cellular membrane in free form. 9,19,20 Based on the highest uptake of Ptx-SLNs into MCF7/ADR compared to Ptx in the other two vehicles, SLNs seemed to be able to enter MDR cells efficiently by bypassing efflux pumps. Consistently with our results, other researchers have also reported that SLNs reversed MDR in drug-resistant MCF7/ADR breast and SKOV3-TR30 ovarian cancer cells by increasing cellular uptake of Ptx and doxorubicin.…”

Section: Discussionmentioning

confidence: 99%

“…18,22,23 Endocytosis mechanisms are classified into pinocytosis and phagocytosis based on the size of the cargo, and then depending on the protein machinery involved, pinocytosis is divided into macropinocytosis, clathrin-mediated, caveola-mediated, and clathrin-and caveola-independent endocytosis. 9,13,24 Different routes of endocytosis result in varied fates of cargos following internalization: nanoparticles internalized through phagocytosis, macropinocytosis, and clathrin-mediated endocytosis usually end up in lysosomes, while those going through caveola-mediated endocytosis can evade lysosomes, leading cargos to the nucleus. 9,24 In the present study, SLNs did not show any superiority compared with unincorporated free form in intracellular delivery of cargo molecules, such as Ptx and Rho, into drug-sensitive MCF7 cells that did not express Pgp.…”

Section: Discussionmentioning

confidence: 99%

“…9,13,24 Different routes of endocytosis result in varied fates of cargos following internalization: nanoparticles internalized through phagocytosis, macropinocytosis, and clathrin-mediated endocytosis usually end up in lysosomes, while those going through caveola-mediated endocytosis can evade lysosomes, leading cargos to the nucleus. 9,24 In the present study, SLNs did not show any superiority compared with unincorporated free form in intracellular delivery of cargo molecules, such as Ptx and Rho, into drug-sensitive MCF7 cells that did not express Pgp. However, SLNs delivered much more cargo molecules into MCF7/ADR cells, which are MDR cells expressing Pgp, suggesting that MCF7/ADR cells might take up SLNs using different endocytosis pathways from those that MCF7 cells utilize.…”

Section: Discussionmentioning

confidence: 99%

“…For this reason, Pgp is considered a "molecular vacuum cleaner", dragging substrates from the membrane and expelling them outside cells. 9 To overcome MDR, researchers have tried to inhibit Pgp-efflux using chemical inhibitors or by evading the efflux pump by incorporating drugs into nanoparticles. [10][11][12] The expulsion of drug molecules occurs following detention of them within bilayers of cellular membrane and subsequent discharge by Pgp.…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Enhanced anticancer activity and intracellular uptake of paclitaxel-containing solid lipid nanoparticles in multidrug-resistant breast cancer cells

Xu¹,

Bae²,

Lee³

2018

IJN

View full text Add to dashboard Cite

PurposeThe aim of this study was to show enhanced anticancer activity of paclitaxel (Ptx) incorporated into solid lipid nanoparticles (SLNs) and reveal reversal of multidrug resistance (MDR) by SLNs mediated by increased uptake through different entry mechanisms from that in drug-sensitive cells.MethodsAnticancer activity of Ptx incorporated in SLNs (Ptx-SLNs) was measured in the drug-sensitive human breast cancer cell line MCF7 and its MDR variant MCF7/ADR. Cellular uptake of cargo molecules in SLNs was compared using Ptx-SLNs and rhodamine 123-loaded SLNs (Rho-SLNs) in both cell lines. In addition, endocytic uptake was evaluated using genistein (Gen) and chlorpromazine (Cpz) as inhibitors of clathrin- and caveola-mediated endocytosis, respectively.ResultsPtx-SLNs showed remarkably enhanced anticancer activity in MCF7/ADR compared to Ptx delivered in dimethyl sulfoxide (DMSO) and Cremophor EL-based vehicles. SLNs significantly increased intracellular uptake of Ptx and Rho in MCF7/ADR. Western blotting demonstrated that clathrin was expressed in both cell lines, while caveolin 1 was expressed only in MCF7/ADR. In MCF7/ADR, uptake of Ptx-SLNs and Rho-SLNs was reduced by Gen, while there was no change by Cpz, suggesting the involvement of caveola-mediated endocytosis. Size reduction of Rho-SLNs through high-pressure homogenization (Rho-SLNs) appeared to cause a shift of the endocytosis mechanism from a clathrin-independent pathway to a clathrin-dependent one. In contrast to MCF7/ADR, the uptake of SLNs into MCF7 was not changed by Gen or Cpz, suggesting involvement of clathrin- and caveola-independent mechanism for the entry of SLNs.ConclusionMDR was reversed by incorporating drug into SLNs, and the reversal was mediated by increased uptake of SLNs evading efflux pumps in MDR cells. The enhanced uptake could also be due to the use of different endocytosis pathways by SLNs in MDR cells from drug-sensitive cancer cells.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Enhanced anticancer activity and intracellular uptake of paclitaxel-containing solid lipid nanoparticles in multidrug-resistant breast cancer cells

Xu¹,

Bae²,

Lee³

2018

IJN

View full text Add to dashboard Cite

show abstract

“…The human MDR gene family includes MDR1 and MDR2. MDR1 is associated with drug resistance in various types of malignant tumors, but MDR2 cannot cause tumor cells to develop drug resistance (36). P-gp is an important expression product of the MDR gene.…”

Section: Discussionmentioning

confidence: 99%

Mechanisms underlying the increased chemosensitivity of bortezomib-resistant multiple myeloma by silencing nuclear transcription factor Snail1

Huang

Liang

et al. 2018

Oncol Rep

View full text Add to dashboard Cite

The Snail family transcriptional repressor 1 gene (Snail1) was screened in multiple myeloma cells (MMCs) from bortezomib-resistant MM patients and was found to be significantly associated with the development of drugresistance mechanisms. In the present study, we first confirmed that the protein expression of Snail1 in bortezomib-resistant MMCs was significantly higher than that in MMCs without bortezomib resistance. The mechanistic studies confirmed that the enhancement of Snail1 expression in bortezomib-resistant MMCs directly upregulated transcription of the intracellular MDR1 gene to immediately develop multiple drug resistance mechanisms and inhibited P53 protein expression through the Snail1/hsa-miRNA-22-3p/P53 pathway to inhibit tumor cell apoptosis. By upregulating MDR1 and downregulating P53, Snail1 induced the drug resistance of MMCs to bortezomib, while Snail1 gene silencing effectively improved the drug sensitivity of MMCs to bortezomib chemotherapy. The present study further elucidated the drug resistance mechanisms of MMCs and provides evidence for increased clinical efficacy of bortezomib in MM patients.

show abstract

Robust Dual Enzyme Cascade‐Catalytic Cholesterol Depletion for Reverse Tumor Multidrug Resistance

Guo

Huang

et al. 2022

Adv Healthcare Materials

View full text Add to dashboard Cite

Although combination drugs and P-glycoprotein inhibitors are the main methods to solve multidrug resistance, these methods ignore the pathological structure of drug-resistant cells and extremely limit curative effect. Herein, a new paradigm of reversing multidrug resistance with abnormal expression of cholesterol as the target is proposed, which uses the cascade catalysis of "natural enzyme" cholesterol oxidase (COD) and "nanoenzyme" Cu 2+ -modified zirconium-based metal-organic framework (ZrMOF(Cu)) to convert cholesterol into the highly cytotoxic hydroxyl radicals. The doxorubicin (DOX)-loaded nanoparticles (DOX@COD-MOF) can significantly reduce the cholesterol content of cancer cells via COD, which decrease the rigidity of drug resistant cancer cell membranes and restore the sensitivity of multidrug-resistant cells to DOX. Afterward, DOX@COD-MOF is encapsulated by cancer cell membranes (CCM) to construct a bionic "dual enzyme catalytic cascade nanoreactor" (DOX@COD-MOF@CCM). Such a rational design presents a preferential accumulation tendency to tumor sites due to the homologous targeting mechanism of CCM, and affords 94.4% in tumor growth suppression without systemic toxicity in vivo. This work aims to achieve the therapeutic purpose of high efficiency and low toxicity. It has the characteristics of "converting enemy into friend, " and opens up a promising way for effectively reversing multidrug resistance of tumors.

show abstract

MDR in cancer: Addressing the underlying cellular alterations with the use of nanocarriers

Cited by 53 publications

References 320 publications

Enhanced anticancer activity and intracellular uptake of paclitaxel-containing solid lipid nanoparticles in multidrug-resistant breast cancer cells

Enhanced anticancer activity and intracellular uptake of paclitaxel-containing solid lipid nanoparticles in multidrug-resistant breast cancer cells

Mechanisms underlying the increased chemosensitivity of bortezomib-resistant multiple myeloma by silencing nuclear transcription factor Snail1

Robust Dual Enzyme Cascade‐Catalytic Cholesterol Depletion for Reverse Tumor Multidrug Resistance

Contact Info

Product

Resources

About