Reversing Chemotherapy Resistance by a Synergy between Lysosomal pH-Activated Mitochondrial Drug Delivery and Erlotinib-Mediated Drug Efflux Inhibition

2021 ◽  
Author(s):  
Furong Cheng ◽  
Qingqing Pan ◽  
Wenxia Gao ◽  
Yuji Pu ◽  
Kui Luo ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Chemotherapy Resistance ◽  
Drug Efflux ◽  
Lysosomal Ph ◽  
Efflux Inhibition

Dual pH-triggered multistage drug delivery systems based on host–guest interaction-associated polymeric nanogels

2014 ◽  
Vol 50 (58) ◽  
pp. 7824-7827 ◽  
Author(s):  
Minghui Zan ◽  
Junjie Li ◽  
Shizhong Luo ◽  
Zhishen Ge
Keyword(s):  
Drug Delivery ◽  
Drug Release ◽  
Drug Delivery Systems ◽  
High Efficiency ◽  
Delivery Systems ◽  
Ph Responsive ◽  
Tissue Penetration ◽  
Deep Tissue ◽  
Lysosomal Ph ◽  
Tumor Acidity

The multistage polymeric nanogel delivery systems were constructed via host–guest interactions, which showed tumor acidity-triggered disassembly into smaller nanoparticles for deep tissue penetration, high-efficiency cellular uptake, and intracellular endo-lysosomal pH-responsive drug release.

SMAR1 repression by pluripotency factors and consequent chemoresistance in breast cancer stem-like cells is reversed by aspirin

2020 ◽  
Vol 13 (654) ◽  
pp. eaay6077
Author(s):  
Apoorva Bhattacharya ◽  
Shravanti Mukherjee ◽  
Poulami Khan ◽  
Shruti Banerjee ◽  
Apratim Dutta ◽  
...  
Keyword(s):  
Efflux Pump ◽  
Chemotherapy Resistance ◽  
Cooperative Interaction ◽  
Drug Efflux ◽  
Cancer Stemness ◽  
Gene Encoding ◽  
Pluripotency Factors ◽  
Tumor Bearing ◽  
Drug Efflux Pumps ◽  
Drug Efflux Pump

The high abundance of drug efflux pumps in cancer stem cells (CSCs) contributes to chemotherapy resistance. The transcriptional regulator SMAR1 suppresses CSC expansion in colorectal cancer, and increased abundance of SMAR1 is associated with better prognosis. Here, we found in breast tumors that the expression of SMAR1 was decreased in CSCs through the cooperative interaction of the pluripotency factors Oct4 and Sox2 with the histone deacetylase HDAC1. Overexpressing SMAR1 sensitized CSCs to chemotherapy through SMAR1-dependent recruitment of HDAC2 to the promoter of the gene encoding the drug efflux pump ABCG2. Treating cultured CSCs or 4T1 tumor-bearing mice with the nonsteroidal anti-inflammatory drug aspirin restored SMAR1 expression and ABCG2 repression and enhanced tumor sensitivity to doxorubicin. Our findings reveal transcriptional mechanisms regulating SMAR1 that also regulate cancer stemness and chemoresistance and suggest that, by restoring SMAR1 expression, aspirin might enhance chemotherapeutic efficacy in patients with stem-like tumors.

scholarly journals Mechanisms of Chemotherapy Resistance in Triple-Negative Breast Cancer—How We Can Rise to the Challenge

Cells ◽  
2019 ◽  
Vol 8 (9) ◽  
pp. 957 ◽  
Author(s):  
Milica Nedeljković ◽  
Ana Damjanović
Keyword(s):  
Breast Cancer ◽  
Triple Negative ◽  
Treatment Options ◽  
Chemotherapy Resistance ◽  
Standard Of Care ◽  
Drug Efflux ◽  
Molecular Signatures ◽  
Chemotherapy Treatment ◽  
Multiple Signaling

Triple-negative (TNBC) is the most lethal subtype of breast cancer owing to high heterogeneity, aggressive nature, and lack of treatment options. Chemotherapy remains the standard of care for TNBC treatment, but unfortunately, patients frequently develop resistance. Accordingly, in recent years, tremendous effort has been made into elucidating the mechanisms of TNBC chemoresistance with the goal of identifying new molecular targets. It has become evident that the development of TNBC chemoresistance is multifaceted and based on the elaborate interplay of the tumor microenvironment, drug efflux, cancer stem cells, and bulk tumor cells. Alterations of multiple signaling pathways govern these interactions. Moreover, TNBC’s high heterogeneity, highlighted in the existence of several molecular signatures, presents a significant obstacle to successful treatment. In the present, in-depth review, we explore the contribution of key mechanisms to TNBC chemoresistance as well as emerging strategies to overcome them. We discuss novel anti-tumor agents that target the components of these mechanisms and pay special attention to their current clinical development while emphasizing the challenges still ahead of successful TNBC management. The evidence presented in this review outlines the role of crucial pathways in TNBC survival following chemotherapy treatment and highlights the importance of using combinatorial drug strategies and incorporating biomarkers in clinical studies.

scholarly journals CSIG-32. DUAL PI3K/Akt INHIBITION TO OVERCOME THE P-gp/BCRP DRUG EFFLUX SYSTEM FOR IMPROVED DRUG DELIVERY IN GLIOBLASTOMA THERAPY

2018 ◽  
Vol 20 (suppl_6) ◽  
pp. vi50-vi50
Author(s):  
Anika Hartz ◽  
Julia Schulz ◽  
Brent Sokola ◽  
Bjoern Bauer
Keyword(s):  
Drug Delivery ◽  
Drug Efflux ◽  
Efflux System

scholarly journals Overcoming chemotherapy resistance via simultaneous drug-efflux circumvention and mitochondrial targeting

2019 ◽  
Vol 9 (3) ◽  
pp. 615-625 ◽  
Author(s):  
Minglu Zhou ◽  
Lijia Li ◽  
Lian Li ◽  
Xi Lin ◽  
Fengling Wang ◽  
...  
Keyword(s):  
Chemotherapy Resistance ◽  
Drug Efflux ◽  
Mitochondrial Targeting

scholarly journals CADD-16. DUAL PI3K/Akt INHIBITION TO OVERCOME THE P-gp/BCRP DRUG EFFLUX SYSTEM FOR IMPROVED DRUG DELIVERY IN GLIOBLASTOMA THERAPY

2018 ◽  
Vol 20 (suppl_6) ◽  
pp. vi279-vi279
Author(s):  
Anika Hartz ◽  
Julia Schulz ◽  
Brent Sokola ◽  
Bjoern Bauer
Keyword(s):  
Drug Delivery ◽  
Drug Efflux ◽  
Efflux System

INCREASING ANTITUMOR EFFECTS OF CHEMORADIOTHERAPY BY DRUG EFFLUX INHIBITION WITH ENCAPSULATED ANTI-RLIP-76

2011 ◽  
Vol 21 (01n02) ◽  
pp. 39-46 ◽  
Author(s):  
S. HARADA ◽  
S. EHARA ◽  
K. ISHII ◽  
H. YAMAZAKI ◽  
S. MATSUYAMA ◽  
...  
Keyword(s):  
Adverse Effects ◽  
Antitumor Effect ◽  
Tumor Tissue ◽  
Chemotherapeutic Agent ◽  
Drug Efflux ◽  
Antitumor Effects ◽  
X Ray ◽  
Tumor Irradiation ◽  
Efflux Inhibition

Microencapsulated anti-RLIP76 was tested in vivo using C 3 He / J mice to determine the increasing of antitumor effects by chemotherapeutic agent efflux inhibition during chemoradiotherapy. Microcapsules were produced by spraying a mixture of 3.0% hyaluronic acid, 2.0% alginate, 3.0% H 2 O 2, and 0.3 mmol carboplatin onto a mixture of 0.3 mol FeCl 2 and 0.15 mol CaCl 2. Microcapsules were subcutaneously injected into MM46 tumors previously inoculated into the left hind legs of C 3 He / J mice. Subsequent radiotherapy consisted of tumor irradiation with 10 Gy or 20 Gy 60 Co . The antitumor effects of microcapsules were tested by measuring tumor size and monitoring tumor growth. Three types of adverse effects were considered: fuzzy hair, loss of body weight, and mortality. Carboplatin levels were monitored using particle-induced X-ray emission (PIXE) and a micro-PIXE camera. Anti-RLIP76 inhibited the efflux of carboplatin from tumor tissue, which led to an increase in the concentration of carboplatin. Higher carboplatin concentration significantly increased the combined antitumor effect of radiation and chemotherapy. A significant decrease in adverse effects was also observed with microencapsulated anti-RLIP76.

scholarly journals Methiothepin Increases Chemotherapy Efficacy against Resistant Melanoma Cells

Molecules ◽  
2021 ◽  
Vol 26 (7) ◽  
pp. 1867
Author(s):  
Nelly Durand ◽  
Méliné Simsir ◽  
Laurie Signetti ◽  
Fabien Labbal ◽  
Robert Ballotti ◽  
...  
Keyword(s):  
Melanoma Cells ◽  
Carcinoma Cells ◽  
Drug Efflux ◽  
Cancer Treatments ◽  
Anti Cancer ◽  
Efflux Inhibition ◽  
Melanoma Patients ◽  
Almost All ◽  
Chemotherapy Efficacy ◽  
Cells Death

We previously reported that methiothepin, a small molecule known as a nonselective serotonin 5-HT receptor antagonist, inhibited the doxorubicin efflux activity of the Hedgehog receptor Ptch1 and enhanced the cytotoxic, pro-apoptotic, anti-proliferative, and anti-clonogenic effects of doxorubicin on adrenocortical carcinoma cells. Here, we show that methiothepin also inhibits doxorubicin efflux and increases doxorubicin cytotoxicity in melanoma cells which endogenously overexpress Ptch1. Melanoma patients having the BRAFV600E mutation are treated with vemurafenib, an inhibitor of BRAFV600E, often in combination with trametinib, an inhibitor of MEK. Almost all patients ultimately acquire resistance to the treatment leading to disease progression. Here, we report that methiothepin overcomes the resistance of BRAFV600E melanoma cells by enhancing the cytotoxicity of vemurafenib and trametinib on these cells leading to melanoma cells death. We observe that the addition of methiothepin to vemurafenib prevents migration of resistant melanoma cells more efficiently than vemurafenib alone. Our results provide an additional proof that Ptch1 drug efflux inhibition increases the effectiveness of anti-cancer treatments and overcomes resistance of melanoma cells expressing Ptch1.

scholarly journals Efflux Inhibition with Verapamil Potentiates Bedaquiline in Mycobacterium tuberculosis

2013 ◽  
Vol 58 (1) ◽  
pp. 574-576 ◽  
Author(s):  
Shashank Gupta ◽  
Keira A. Cohen ◽  
Kathryn Winglee ◽  
Mamoudou Maiga ◽  
Bassirou Diarra ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Resistance Mechanism ◽  
Clinical Isolates ◽  
Drug Efflux ◽  
Drug Resistant ◽  
Content Type ◽  
Efflux Inhibition

ABSTRACTDrug efflux is an important resistance mechanism inMycobacterium tuberculosis. We found that verapamil, an efflux inhibitor, profoundly decreases the MIC of bedaquiline and clofazimine toM. tuberculosisby 8- to 16-fold. This exquisite susceptibility was noted among drug-susceptible and drug-resistant clinical isolates. Thus, efflux inhibition is an important sensitizer of bedaquiline and clofazimine, and efflux may emerge as a resistance mechanism to these drugs.

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