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.

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.

scholarly journals Dual Targeting of Cancer Cells and MMPs with Self-Assembly Hybrid Nanoparticles for Combination Therapy in Combating Cancer

Pharmaceutics ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 1990
Author(s):  
Kai Zhang ◽  
Jingjing Li ◽  
Xiaofei Xin ◽  
Xiaoqing Du ◽  
Di Zhao ◽  
...  
Keyword(s):  
T Cells ◽  
Cancer Cells ◽  
Self Assembly ◽  
Chemotherapeutic Agents ◽  
Hybrid Nanoparticles ◽  
Control Group ◽  
Hyperthermia Treatment ◽  
Immune Modulators ◽  
Dual Targeting

The co-delivery of chemotherapeutic agents and immune modulators to their targets remains to be a great challenge for nanocarriers. Here, we developed a hybrid thermosensitive nanoparticle (TMNP) which could co-deliver paclitaxel-loaded transferrin (PTX@TF) and marimastat-loaded thermosensitive liposomes (MMST/LTSLs) for the dual targeting of cancer cells and the microenvironment. TMNPs could rapidly release the two payloads triggered by the hyperthermia treatment at the site of tumor. The released PTX@TF entered cancer cells via transferrin-receptor-mediated endocytosis and inhibited the survival of tumor cells. MMST was intelligently employed as an immunomodulator to improve immunotherapy by inhibiting matrix metalloproteinases to reduce chemokine degradation and recruit T cells. The TMNPs promoted the tumor infiltration of CD3+ T cells by 2-fold, including memory/effector CD8+ T cells (4.2-fold) and CD4+ (1.7-fold), but not regulatory T cells. Our in vivo anti-tumor experiment suggested that TMNPs possessed the highest tumor growth inhibitory rate (80.86%) compared with the control group. We demonstrated that the nanoplatform could effectively inhibit the growth of tumors and enhance T cell recruitment through the co-delivery of paclitaxel and marimastat, which could be a promising strategy for the combination of chemotherapy and immunotherapy for cancer treatment.

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 Cisplatin Synergistically Enhances Antitumor Potency of Conditionally Replicating Adenovirus via p53 Dependent or Independent Pathways in Human Lung Carcinoma

2019 ◽  
Vol 20 (5) ◽  
pp. 1125 ◽  
Author(s):  
Sakhawat Ali ◽  
Muhammad Tahir ◽  
Aamir Khan ◽  
Xue Chen ◽  
Ma Ling ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cancer Cells ◽  
Combined Treatment ◽  
Acquired Resistance ◽  
Chemotherapy Resistance ◽  
Chemotherapeutic Agents ◽  
Lung Cancer Cells ◽  
Advanced Lung Cancer ◽  
Mesenchymal Transition ◽  
Conditionally Replicating Adenovirus

Cisplatin is ranked as one of the most powerful and commonly prescribed anti-tumor chemotherapeutic agents which improve survival in many solid tumors including non-small cell lung cancer. However, the treatment of advanced lung cancer is restricted due to chemotherapy resistance. Here, we developed and investigated survivin promoter regulating conditionally replicating adenovirus (CRAd) for its anti-tumor potential alone or in combination with cisplatin in two lung cancer cells, H23, H2126, and their resistant cells, H23/CPR, H2126/CPR. To measure the expression of genes which regulate resistance, adenoviral transduction, metastasis, and apoptosis in cancer cells, RT-PCR and Western blotting were performed. The anti-tumor efficacy of the treatments was evaluated through flow cytometry, MTT and transwell assays. This study demonstrated that co-treatment with cisplatin and CRAd exerts synergistic anti-tumor effects on chemotherapy sensitive lung cancer cells and monotherapy of CRAd could be a practical approach to deal with chemotherapy resistance. Combined treatment induced stronger apoptosis by suppressing the anti-apoptotic molecule Bcl-2, and reversed epithelial to mesenchymal transition. In conclusion, cisplatin synergistically increased the tumor-killing of CRAd by (1) increasing CRAd transduction via enhanced CAR expression and (2) increasing p53 dependent or independent apoptosis of lung cancer cell lines. Also, CRAd alone proved to be a very efficient anti-tumor agent in cancer cells resistant to cisplatin owing to upregulated CAR levels. In an exciting outcome, we have revealed novel therapeutic opportunities to exploit intrinsic and acquired resistance to enhance the therapeutic index of anti-tumor treatment in lung cancer.

scholarly journals Chemotherapeutic drugs stimulate the release and recycling of extracellular vesicles to assist cancer cells in developing an urgent chemoresistance

2019 ◽  
Vol 18 (1) ◽  
Author(s):  
Xiaokun Wang ◽  
Dongjuan Qiao ◽  
Likun Chen ◽  
Meng Xu ◽  
Shupeng Chen ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Extracellular Vesicles ◽  
Small Cell Lung Carcinoma ◽  
Underlying Mechanism ◽  
Chemotherapeutic Agents ◽  
Chemotherapeutic Drugs ◽  
Xenograft Tumor ◽  
Tumor Models ◽  
Cell Lung Carcinoma

Abstract Background Chemotherapy is a widely used treatment for cancer. However, the development of acquired multidrug resistance (MDR) is a serious issue. Emerging evidence has shown that the extracellular vesicles (EVs) mediate MDR, but the underlying mechanism remains unclear, especially the effects of chemotherapeutic agents on this process. Methods Extracellular vesicles isolation was performed by differential centrifugation. The recipient cells that acquired ATP-binding cassette sub-family B member 1 (ABCB1) proteins were sorted out from co-cultures according to a stringent multi-parameter gating strategy by fluorescence-activated cell sorting (FACS). The transfer rate of ABCB1 was measured by flow cytometry. The xenograft tumor models in mice were established to evaluate the transfer of ABCB1 in vivo. Gene expression was detected by real-time PCR and Western blotting. Results Herein, we show that a transient exposure to chemotherapeutic agents can strikingly increase Rab8B-mediated release of extracellular vesicles (EVs) containing ABCB1 from drug-resistant cells, and accelerate these EVs to circulate back onto plasma membrane of sensitive tumor cells via the down-regulation of Rab5. Therefore, intercellular ABCB1 transfer is significantly enhanced; sensitive recipient cells acquire a rapid but unsustainable resistance to evade the cytotoxicity of chemotherapeutic agents. More fascinatingly, in the xenograft tumor models, chemotherapeutical drugs also locally or distantly increase the transfer of ABCB1 molecules. Furthermore, some Non-small-cell lung carcinoma (NSCLC) patients who are undergoing primary chemotherapy have a rapid increase of ABCB1 protein in their monocytes, and this is obviously associated with poor chemotherapeutic efficacy. Conclusions Chemotherapeutic agents stimulate the secretion and recycling of ABCB1-enriched EVs through the dysregulation of Rab8B and Rab5, leading to a significant increase of ABCB1 intercellular transfer, thus assisting sensitive cancer cells to develop an urgent resistant phenotype. Our findings provide a new molecular mechanism of how chemotherapeutic drugs assist sensitive cancer cells in acquiring an urgent resistance.

scholarly journals A Review of the Potential of Phytochemicals from Prunus africana (Hook f.) Kalkman Stem Bark for Chemoprevention and Chemotherapy of Prostate Cancer

2017 ◽  
Vol 2017 ◽  
pp. 1-10 ◽  
Author(s):  
Richard Komakech ◽  
Youngmin Kang ◽  
Jun-Hwan Lee ◽  
Francis Omujal
Keyword(s):  
Prostate Cancer ◽  
Cancer Cells ◽  
Treatment Options ◽  
Chemotherapeutic Agents ◽  
Sub Saharan Africa ◽  
In Vivo Studies ◽  
Prostate Cancer Cells ◽  
Prunus Africana

Prostate cancer remains one of the major causes of death worldwide. In view of the limited treatment options for patients with prostate cancer, preventive and treatment approaches based on natural compounds can play an integral role in tackling this disease. Recent evidence supports the beneficial effects of plant-derived phytochemicals as chemopreventive and chemotherapeutic agents for various cancers, including prostate cancer. Prunus africana has been used for generations in African traditional medicine to treat prostate cancer. This review examined the potential roles of the phytochemicals from P. africana, an endangered, sub-Saharan Africa plant in the chemoprevention and chemotherapy of prostate cancer. In vitro and in vivo studies have provided strong pharmacological evidence for antiprostate cancer activities of P. africana-derived phytochemicals. Through synergistic interactions between different effective phytochemicals, P. africana extracts have been shown to exhibit very strong antiandrogenic and antiangiogenic activities and have the ability to kill tumor cells via apoptotic pathways, prevent the proliferation of prostate cancer cells, and alter the signaling pathways required for the maintenance of prostate cancer cells. However, further preclinical and clinical studies ought to be done to advance and eventually use these promising phytochemicals for the prevention and chemotherapy of human prostate cancer.

scholarly journals Thyroid Hormone and P-Glycoprotein in Tumor Cells

2015 ◽  
Vol 2015 ◽  
pp. 1-8 ◽  
Author(s):  
Paul J. Davis ◽  
Sandra Incerpi ◽  
Hung-Yun Lin ◽  
Heng-Yuan Tang ◽  
Thangirala Sudha ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Molecular Mechanisms ◽  
Efflux Pump ◽  
Inhibitory Effect ◽  
Chemotherapeutic Agents ◽  
Cell Surface Receptor ◽  
P Glycoprotein ◽  
Surface Receptor

P-glycoprotein (P-gp; multidrug resistance pump 1, MDR1; ABCB1) is a plasma membrane efflux pump that when activated in cancer cells exports chemotherapeutic agents. Transcription of the P-gp gene (MDR1) and activity of the P-gp protein are known to be affected by thyroid hormone. A cell surface receptor for thyroid hormone on integrinαvβ3 also binds tetraiodothyroacetic acid (tetrac), a derivative of L-thyroxine (T4) that blocks nongenomic actions of T4and of 3,5,3′-triiodo-L-thyronine (T3) atαvβ3. Covalently bound to a nanoparticle, tetrac as nanotetrac acts at the integrin to increase intracellular residence time of chemotherapeutic agents such as doxorubicin and etoposide that are substrates of P-gp. This action chemosensitizes cancer cells. In this review, we examine possible molecular mechanisms for the inhibitory effect of nanotetrac on P-gp activity. Mechanisms for consideration include cancer cell acidification via action of tetrac/nanotetrac on the Na+/H+exchanger (NHE1) and hormone analogue effects on calmodulin-dependent processes and on interactions of P-gp with epidermal growth factor (EGF) and osteopontin (OPN), apparently viaαvβ3. Intracellular acidification and decreased H+efflux induced by tetrac/nanotetrac via NHE1 is the most attractive explanation for the actions on P-gp and consequent increase in cancer cell retention of chemotherapeutic agent-ligands of MDR1 protein.

scholarly journals Cotargeting Polo-Like Kinase 1 and the Wnt/β-Catenin Signaling Pathway in Castration-Resistant Prostate Cancer

2015 ◽  
Vol 35 (24) ◽  
pp. 4185-4198 ◽  
Author(s):  
Jie Li ◽  
Anju Karki ◽  
Kurt B. Hodges ◽  
Nihal Ahmad ◽  
Amina Zoubeidi ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Cells ◽  
Signaling Pathway ◽  
Glycogen Synthase ◽  
Therapeutic Option ◽  
Negative Regulator ◽  
Castration Resistant Prostate Cancer ◽  
Prostate Cancer Cells ◽  
Castration Resistant

The Wnt/β-catenin signaling pathway has been identified as one of the predominantly upregulated pathways in castration-resistant prostate cancer (CRPC). However, whether targeting the β-catenin pathway will prove effective as a CRPC treatment remains unknown. Polo-like kinase 1 (Plk1) is a critical regulator in many cell cycle events, and its level is significantly elevated upon castration of mice carrying xenograft prostate tumors. Indeed, inhibition of Plk1 has been shown to inhibit tumor growth in severalin vivostudies. Here, we show that Plk1 is a negative regulator of Wnt/β-catenin signaling. Plk1 inhibition or depletion enhances the level of cytosolic and nuclear β-catenin in human prostate cancer cells. Furthermore, inhibition of Wnt/β-catenin signaling significantly potentiates the antineoplastic activity of the Plk1 inhibitor BI2536 in both cultured prostate cancer cells and CRPC xenograft tumors. Mechanistically, axin2, a negative regulator of the β-catenin pathway, serves as a substrate of Plk1, and Plk1 phosphorylation of axin2 facilitates the degradation of β-catenin by enhancing binding between glycogen synthase kinase 3β (GSK3β) and β-catenin. Plk1-phosphorylated axin2 also exhibits resistance to Cdc20-mediated degradation. Overall, this study identifies a novel Plk1-Wnt signaling axis in prostate cancer, offering a promising new therapeutic option to treat CRPC.

scholarly journals Matrine inhibits the development and progression of ovarian cancer by repressing cancer associated phosphorylation signaling pathways

2019 ◽  
Vol 10 (10) ◽  
Author(s):  
Xi Zhang ◽  
Guoqing Hou ◽  
Andong Liu ◽  
Hui Xu ◽  
Yang Guan ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Side Effects ◽  
Cancer Cells ◽  
Signaling Pathways ◽  
Molecular Mechanisms ◽  
Chemotherapy Resistance ◽  
Treatment Strategies ◽  
Ovarian Cancer Cells

Abstract Ovarian cancer remains the most lethal gynecologic malignancy with late detection and acquired chemoresistance. Advanced understanding of the pathophysiology and novel treatment strategies are urgently required. A growing body of proteomic investigations suggest that phosphorylation has a pivotal role in the regulation of ovarian cancer associated signaling pathways. Matrine has been extensively studied for its potent anti-tumor activities. However, its effect on ovarian cancer cells and underlying molecular mechanisms remain unclear. Herein we showed that matrine treatment inhibited the development and progression of ovarian cancer cells by regulating proliferation, apoptosis, autophagy, invasion and angiogenesis. Matrine treatment retarded the cancer associated signaling transduction by decreasing the phosphorylation levels of ERK1/2, MEK1/2, PI3K, Akt, mTOR, FAK, RhoA, VEGFR2, and Tie2 in vitro and in vivo. Moreover, matrine showed excellent antitumor effect on chemoresistant ovarian cancer cells. No obvious toxic side effects were observed in matrine-administrated mice. As the natural agent, matrine has the potential to be the targeting drug against ovarian cancer cells with the advantages of overcoming the chemotherapy resistance and decreasing the toxic side effects.

scholarly journals The REGγ inhibitor NIP30 increases sensitivity to chemotherapy in p53-deficient tumor cells

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Xiao Gao ◽  
Qingwei Wang ◽  
Ying Wang ◽  
Jiang Liu ◽  
Shuang Liu ◽  
...  
Keyword(s):  
Chemotherapy Resistance ◽  
Inhibitory Effect ◽  
Chemotherapeutic Agents ◽  
Serine Phosphorylation ◽  
Cancer Cell Growth ◽  
Rich Domain ◽  
Novel Approach ◽  
Growth Inhibitory

Abstract A major challenge in chemotherapy is chemotherapy resistance in cells lacking p53. Here we demonstrate that NIP30, an inhibitor of the oncogenic REGγ-proteasome, attenuates cancer cell growth and sensitizes p53-compromised cells to chemotherapeutic agents. NIP30 acts by binding to REGγ via an evolutionarily-conserved serine-rich domain with 4-serine phosphorylation. We find the cyclin-dependent phosphatase CDC25A is a key regulator for NIP30 phosphorylation and modulation of REGγ activity during the cell cycle or after DNA damage. We validate CDC25A-NIP30-REGγ mediated regulation of the REGγ target protein p21 in vivo using p53−/− and p53/REGγ double-deficient mice. Moreover, Phosphor-NIP30 mimetics significantly increase the growth inhibitory effect of chemotherapeutic agents in vitro and in vivo. Given that NIP30 is frequently mutated in the TCGA cancer database, our results provide insight into the regulatory pathway controlling the REGγ-proteasome in carcinogenesis and offer a novel approach to drug-resistant cancer therapy.

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