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 Mitochondrial Targeting and pH-Responsive Nanogels for Co-Delivery of Lonidamine and Paclitaxel to Conquer Drug Resistance

2021 ◽  
Vol 9 ◽  
Author(s):  
Enping Chen ◽  
Ting Wang ◽  
Junmei Zhang ◽  
Xiang Zhou ◽  
Yafan Niu ◽  
...  
Keyword(s):  
Drug Loading ◽  
Ph Sensitive ◽  
Combination Regimen ◽  
Drug Efflux ◽  
Drug Resistant ◽  
Oxygen Species ◽  
Chemotherapeutic Drug ◽  
Mitochondrial Targeting ◽  
Ph Responsive ◽  
Mcf 7

Multidrug resistance (MDR) is one of the leading causes of the failure of cancer chemotherapy and mainly attributed to the overexpression of drug efflux transporters in cancer cells, which is dependent on adenosine triphosphate (ATP). To overcome this phenomenon, herein, a mitochondrial-directed pH-sensitive polyvinyl alcohol (PVA) nanogel incorporating the hexokinase inhibitor lonidamine (LND) and the chemotherapeutic drug paclitaxel (PTX) was developed to restore the activity of PTX and synergistically treat drug-resistant tumors. The introduction of 2-dimethylaminoethanethiol (DMA) moiety into the nanogels not only promoted the drug loading capacity but also enabled the lysosomal escape of the nanogels. The subsequent mitochondrial targeting facilitated the accumulation and acid-triggered payload release in the mitochondria. The released LND can destroy the mitochondria by exhausting the mitochondrial membrane potential (MMP), generating reactive oxygen species (ROS) and restraining the energy supply, resulting in apoptosis and susceptibility of the MCF-7/MDR cells to PTX. Hence, the nanogel-enabled combination regimen of LND and PTX showed a boosted anti-tumor efficacy in MCF-7/MDR cells. These mitochondrial-directed pH-sensitive PVA nanogels incorporating both PTX and LND represent a new nanoplatform for MDR reversal and enhanced therapeutic efficacy.

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 Construction of Hierarchical-Targeting pH-Sensitive Liposomes to Reverse Chemotherapeutic Resistance of Cancer Stem-like Cells

Pharmaceutics ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1205
Author(s):  
Shuang Ba ◽  
Mingxi Qiao ◽  
Li Jia ◽  
Jiulong Zhang ◽  
Xiuli Zhao ◽  
...  
Keyword(s):  
Synergistic Effect ◽  
Chemotherapy Resistance ◽  
Tumor Model ◽  
Ph Sensitive ◽  
Mitochondrial Targeting ◽  
Tumor Treatment ◽  
Chemotherapeutic Resistance ◽  
Xenograft Tumor Model ◽  
Tumor Region

Cancer stem-like cells (CSLCs) have been considered to be one of the main problems in tumor treatment owing to high tumorigenicity and chemotherapy resistance. In this study, we synthesized a novel mitochondria-target derivate, triphentlphosphonium-resveratrol (TPP-Res), and simultaneously encapsulated it with doxorubicin (Dox) in pH-sensitive liposomes (PSL (Dox/TPP-Res)), to reverse chemotherapeutic resistance of CSLCs. PSL (Dox/TPP-Res) was approximately 165 nm in size with high encapsulation efficiency for both Dox and TPP-Res. Cytotoxicity assay showed that the optimal synergistic effect was the drug ratio of 1:1 for TPP-Res and Dox. Cellular uptake and intracellular trafficking assay indicated that PSL (Dox/TPP-Res) could release drugs in acidic endosomes, followed by mitochondrial targeting of TPP-Res and nucleus transports for Dox. The mechanisms for reversing the resistance in CSLCs were mainly attributed to a synergistic effect for reduction of mitochondrial membrane potential, activation of caspase cascade reaction, reduction of ATP level and suppression of the Wnt/β-catenin pathway. Further, in vivo assay results demonstrated that the constructed liposomes could efficiently accumulate in the tumor region and possess excellent antineoplastic activity in an orthotopic xenograft tumor model with no evident systemic toxicity. The above experimental results determined that PSL (Dox/TPP-Res) provides a new method for the treatment of heterogenecity tumors.

scholarly journals Targeting the Multidrug Transporter Ptch1 Potentiates Chemotherapy Efficiency

Cells ◽  
2018 ◽  
Vol 7 (8) ◽  
pp. 107 ◽  
Author(s):  
Anida Hasanovic ◽  
Isabelle Mus-Veteau
Keyword(s):  
Cancer Cells ◽  
Abc Transporters ◽  
Adrenocortical Carcinoma ◽  
Efflux Pump ◽  
Therapeutic Option ◽  
Chemotherapy Resistance ◽  
Chemotherapeutic Agents ◽  
Multidrug Transporter ◽  
Drug Efflux

One of the crucial challenges in the clinical management of cancer is resistance to chemotherapeutics. Multidrug resistance (MDR) has been intensively studied, and one of the most prominent mechanisms underlying MDR is overexpression of adenosine triphosphate (ATP)-binding cassette (ABC) transporters. Despite research efforts to develop compounds that inhibit the efflux activity of ABC transporters and thereby increase classical chemotherapy efficacy, to date, the Food and Drug Administration (FDA) has not approved the use of any ABC transporter inhibitors due to toxicity issues. Hedgehog signaling is aberrantly activated in many cancers, and has been shown to be involved in chemotherapy resistance. Recent studies showed that the Hedgehog receptor Ptch1, which is over-expressed in many recurrent and metastatic cancers, is a multidrug transporter and it contributes to the efflux of chemotherapeutic agents such as doxorubicin, and to chemotherapy resistance. Remarkably, Ptch1 uses the proton motive force to efflux drugs, in contrast to ABC transporters, which use ATP hydrolysis. Indeed, the “reversed pH gradient” that characterizes cancer cells, allows Ptch1 to function as an efflux pump specifically in cancer cells. This makes Ptch1 a particularly attractive therapeutic target for cancers expressing Ptch1, such as lung, breast, prostate, ovary, colon, brain, adrenocortical carcinoma, and melanoma. Screening of chemical libraries have identified several molecules that are able to enhance the cytotoxic effect of different chemotherapeutic agents by inhibiting Ptch1 drug efflux activity in different cancer cell lines that endogenously over-express Ptch1. In vivo proof of concept has been performed in mice where combining one of these compounds with doxorubicin prevented the development of xenografted adrenocortical carcinoma tumors more efficiently than doxorubicin alone, and without obvious undesirable side effects. Therefore, the use of a Ptch1 drug efflux inhibitor in combination with classical or targeted therapy could be a promising therapeutic option for Ptch1-expressing cancers.

Multifunctional Nano-Delivery System Enhances the Chemo-co-Photo Therapy of Tumor Multidrug Resistance via Mitochondrial-Targeting and Inhibiting P-glycoprotein-Mediated Efflux

2021 ◽  
Author(s):  
Runze Zhao ◽  
Xiaoyue Ning ◽  
Mengqi Wang ◽  
Ao Yu ◽  
Yongjian Wang
Keyword(s):  
Multidrug Resistance ◽  
Delivery System ◽  
Multidrug Resistant ◽  
Drug Efflux ◽  
Mitochondrial Targeting ◽  
Tumor Treatment ◽  
P Glycoprotein ◽  
Multidrug Resistant Tumors

Despite the excellent progress of chemotherapy and phototherapy in tumor treatment, their effectiveness on multidrug-resistant tumors (MDR) is still unsatisfactory. One of the main obstacles is drug efflux caused by...

scholarly journals RND family efflux pumps: from antibioresistance to chemotherapy resistance

2020 ◽  
Vol 1 (1) ◽  
pp. 51-61
Author(s):  
Méliné Simsir ◽  
◽  
Isabelle Mus-Veteau ◽  
Keyword(s):  
Multidrug Resistance ◽  
Cancer Cells ◽  
Abc Transporters ◽  
Chemotherapy Resistance ◽  
Drug Efflux ◽  
Efflux Mechanism ◽  
The Common ◽  
Chemotherapeutic Treatment ◽  
Over 40 Years

Resistance to chemotherapy can be studied comparatively to the study of resistance in microorganisms. For over 40 years, understanding mechanisms that confer MDR has been a major goal of cancer biologists. Most of the studies toward MDR in cancer cells were about ABC transporters. Unfortunately, inhibition of these transporters often resulted in over toxicity due to the important role of these ABC transporters in healthy cells. The discovery of other targets for MDR of resistant cancer cells is of significant interest. Among the protein superfamily identified as being responsible for multidrug resistance are RND. Its members are widespread in bacterial organisms, but also in Archaea and Eukaryotes. Among the common features of multidrug resistance in RND is the ability of these transmembrane proteins to efflux a broad spectrum of substrates and drugs using the proton motive force. Ptch1, member of the RND family, is overexpressed in many aggressive and metastatic cancers. Like other members of the RND family such as NPC1, it is able to transport cholesterol. It was later shown to transport chemotherapeutic drugs, and its inhibition in resistant cancer cell lines resulted in increasing chemotherapeutic treatment efficacy. However, the drug efflux mechanism of Ptch1 is still unknown. In this review, we will discuss the possibility of a drug efflux mechanism common to the different proteins from the RND family.

Crystal structures of plant inorganic pyrophosphatase, an enzyme with a moonlighting autoproteolytic activity

2019 ◽  
Vol 476 (16) ◽  
pp. 2297-2319 ◽  
Author(s):  
Marta Grzechowiak ◽  
Milosz Ruszkowski ◽  
Joanna Sliwiak ◽  
Kamil Szpotkowski ◽  
Michal Sikorski ◽  
...  
Keyword(s):  
Site Directed Mutagenesis ◽  
Size Exclusion ◽  
Inorganic Pyrophosphatase ◽  
Prolonged Storage ◽  
Mitochondrial Targeting ◽  
Cleavage Rate ◽  
Inorganic Pyrophosphate ◽  
Putative Signal Peptide ◽  
Targeting Peptide

Abstract Inorganic pyrophosphatases (PPases, EC 3.6.1.1), which hydrolyze inorganic pyrophosphate to phosphate in the presence of divalent metal cations, play a key role in maintaining phosphorus homeostasis in cells. DNA coding inorganic pyrophosphatases from Arabidopsis thaliana (AtPPA1) and Medicago truncatula (MtPPA1) were cloned into a bacterial expression vector and the proteins were produced in Escherichia coli cells and crystallized. In terms of their subunit fold, AtPPA1 and MtPPA1 are reminiscent of other members of Family I soluble pyrophosphatases from bacteria and yeast. Like their bacterial orthologs, both plant PPases form hexamers, as confirmed in solution by multi-angle light scattering and size-exclusion chromatography. This is in contrast with the fungal counterparts, which are dimeric. Unexpectedly, the crystallized AtPPA1 and MtPPA1 proteins lack ∼30 amino acid residues at their N-termini, as independently confirmed by chemical sequencing. In vitro, self-cleavage of the recombinant proteins is observed after prolonged storage or during crystallization. The cleaved fragment corresponds to a putative signal peptide of mitochondrial targeting, with a predicted cleavage site at Val31–Ala32. Site-directed mutagenesis shows that mutations of the key active site Asp residues dramatically reduce the cleavage rate, which suggests a moonlighting proteolytic activity. Moreover, the discovery of autoproteolytic cleavage of a mitochondrial targeting peptide would change our perception of this signaling process.

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