scholarly journals Rutaecarpine Increases Anticancer Drug Sensitivity in Drug-Resistant Cells through MARCH8-Dependent ABCB1 Degradation

Biomedicines ◽  
2021 ◽  
Vol 9 (9) ◽  
pp. 1143
Author(s):  
Tingting Zou ◽  
Cheng Zeng ◽  
Junyan Qu ◽  
Xiaohua Yan ◽  
Zhenghong Lin
Keyword(s):  
Therapeutic Effect ◽  
Ubiquitin Ligase ◽  
Protein Level ◽  
Drug Sensitivity ◽  
Chemotherapeutic Agents ◽  
Chemotherapeutic Drugs ◽  
Transplanted Tumors ◽  
Reversal Effect ◽  
P Glycoprotein ◽  
Evodia Rutaecarpa

The overexpression of adenosine triphosphate (ATP)-binding cassette (ABC) subfamily B member 1 (ABCB1; P-glycoprotein; MDR1) in some types of cancer cells is one of the mechanisms responsible for the development of multidrug resistance (MDR), which leads to the failure of chemotherapy. Therefore, it is important to inhibit the activity or reduce the expression level of ABCB1 to maintain an effective intracellular level of chemotherapeutic drugs. In this study, we found that rutaecarpine, a bioactive alkaloid isolated from Evodia Rutaecarpa, has the capacity to reverse ABCB1-mediated MDR. Our data indicated that the reversal effect of rutaecarpine was related to the attenuation of the protein level of ABCB1. Mechanistically, we demonstrated that ABCB1 is a newly discovered substrate of E3 ubiquitin ligase membrane-associated RING-CH 8 (MARCH8). MARCH8 can interact with ABCB1 and promote its ubiquitination and degradation. In short, rutaecarpine increased the degradation of ABCB1 protein by upregulating the protein level of MARCH8, thereby antagonizing ABCB1-mediated MDR. Notably, the treatment of rutaecarpine combined with other anticancer drugs exhibits a therapeutic effect on transplanted tumors. Therefore, our study provides a potential chemotherapeutic strategy of co-administrating rutaecarpine with other conventional chemotherapeutic agents to overcome MDR and improve therapeutic effect.

Combination Therapy of Cisplatin and Other Agents for Osteosarcoma: A Review

2020 ◽  
Vol 16 ◽  
Author(s):  
Mohamad Zahid Kasiram ◽  
Hermizi Hapidin ◽  
Hasmah Abdullah ◽  
Azlina Ahmad ◽  
Sarina Sulong
Keyword(s):  
Radiation Therapy ◽  
Survival Rate ◽  
Chemotherapeutic Agents ◽  
New Combination ◽  
Rapid Progression ◽  
Combination Regimen ◽  
Chemotherapeutic Drugs ◽  
Primary Bone Tumor ◽  
Phytochemical Compounds

Background: Osteosarcoma is the most common type of primary bone tumor in children and adolescents, which is associated with rapid progression and poor prognosis. Multimodal therapy is the most common approach utilized for osteosarcoma management, such as the application of chemotherapy in combination with surgery or radiation therapy. Cisplatin is one of the predominantly used chemotherapeutic agents for osteosarcoma. Optimally, it is employed in combination with other chemotherapeutic drugs along with surgery or radiation therapy. Despite the availability of numerous treatment approaches, patient survival rate has not definitively improved over the past three decades. Methods: We summarized all findings regarding the combination of cisplatin with other chemotherapeutic agents as well as with phytochemical compounds. Results: A combination of cisplatin with phytochemical compound synergistically enhances the killing effect of cisplatin on osteosarcoma cells with fewer side effects compared to combination with other chemotherapeutic agents. Conclusion: Conclusively, a combination of cisplatin with selected chemotherapeutic drugs, has been shown to be effective. However, the unchanged survival rate urges for the search of a new combination regimen. As a collaborative effort to substantiate the therapeutic efficacy, the combination with phytochemical compounds shows a promising response both in vitro as well as in the preclinical study.

Kinetics of the multidrug transporter (P-glycoprotein) and its reversal

1997 ◽  
Vol 77 (2) ◽  
pp. 545-590 ◽  
Author(s):  
W. D. Stein
Keyword(s):  
Final Section ◽  
Transport Kinetics ◽  
Multidrug Transporter ◽  
Chemotherapeutic Drugs ◽  
Multidrug Resistance Proteins ◽  
Binding Properties ◽  
Membrane Pump ◽  
Resistance Proteins ◽  
P Glycoprotein ◽  
Kinetics Of

Most cancer deaths result from the cancer's either being intrinsically resistant to chemotherapeutic drugs or becoming resistant after being initially sensitive. Often, in cells grown in cell culture, drug resistance correlates with the presence of one or more of the so-called P-glycoproteins or multidrug resistance proteins, products of the mdr family of genes. This review is largely concerned with the transport kinetics of the P-glycoproteins. We first present a brief overview of the P-glycoproteins, their properties, and their clinical significance. Later sections of the review expand on this material with special emphasis on the substrates of P-glycoprotein and how they cross the cell membrane, on the transport kinetics of the P-glycoprotein, on reversers of its action, and on its activity as an ATPase. In a final section, we consider the mechanism of action of P-glycoprotein as an actively transporting membrane pump. The characteristic of P-glycoprotein considered the most difficult to explain is its very broad specificity (or lack of specificity), but there are precedents for this property in well-known proteins such as serum albumin, which binds a range of molecular types, including substrates and reversers of P-glycoprotein, seemingly as broad as does P-glycoprotein. Pointing out this analogy does not provide a molecular explanation for the substrate-binding properties of P-glycoprotein but does make those properties more assimilable.

scholarly journals Secondary Metabolites from Saccharomyces cerevisiae Species with Anticancer Potential

2021 ◽  
Author(s):  
Muhammad Jahangeer ◽  
Areej Riasat ◽  
Zahed Mahmood ◽  
Muhammad Numan ◽  
Naveed Munir ◽  
...  
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Secondary Metabolites ◽  
Apoptotic Cell ◽  
Inhibitory Effect ◽  
Chemotherapeutic Agents ◽  
Chemotherapeutic Drugs ◽  
Central Metabolism ◽  
Biotic Stresses ◽  
Micro Organisms ◽  
New Chemotherapeutic Agents

Chemotherapeutic agents produce from numerous sources such as animals, plants and micro-organisms are derived from the natural products. Although the existing therapeutic pipeline lacks fungal-derived metabolites, but hundreds of secondary metabolites derived from fungi are known to be possible chemotherapies. Over the past three decades, several secondary metabolites such as flavonoids, alkaloids, phenolic and polyketides have been developed by Saccharomyces cerevisiae species with exciting activities that considered valued for the growth of new chemotherapeutic agents. Many secondary metabolites are protective compounds which prevent abiotic and biotic stresses, i.e. predation, infection, drought and ultraviolet. Though not taking part in a living cell’s central metabolism, secondary metabolites play an important role in the function of an organism. Nevertheless, due to slow biomass build-up and inadequate synthesis by the natural host the yield of secondary metabolites is low by direct isolation. A detailed comprehension of biosynthetic pathways for development of secondary metabolites are necessary for S. cerevisiae biotransformation. These metabolites have higher inhibitory effect, specificity among cancer and normal cells, and the mechanism of non-apoptotic cell killing. This study shows the significance of bioactive compounds produced by S. cerevisiae species with their possible activity and value in chemotherapeutic drugs pipeline. The isolation and alteration of these natural secondary metabolites would promote the development of chemotherapeutic drugs.

Antitumor Therapeutic Effect of Neurotropin on Transplanted Tumors in Rats

Oncology ◽  
1984 ◽  
Vol 41 (4) ◽  
pp. 289-292 ◽  
Author(s):  
Yutaka Mizushima ◽  
Terry Wepsic ◽  
Hiroshi Kobayashi
Keyword(s):  
Therapeutic Effect ◽  
Transplanted Tumors

Reversal of chemoresistance in malignant gliomas by calcium antagonists: correlation with the expression of multidrug-resistant p-glycoprotein

1994 ◽  
Vol 81 (4) ◽  
pp. 587-594 ◽  
Author(s):  
Jurgen Carl Walther Kiwit ◽  
Anja Hertel ◽  
Alexander E. Matuschek
Keyword(s):  
Calcium Antagonists ◽  
Malignant Gliomas ◽  
Multidrug Resistant ◽  
Chemotherapeutic Agents ◽  
Positive Staining ◽  
Glycoprotein P ◽  
Content Type ◽  
P Glycoprotein ◽  
Multiple Drugs

✓ Resistance to multiple drugs is often observed in malignant gliomas. The authors used a microtiter tetrazolium test to analyze primary in vitro chemoresistance and chemosensitivity of 15 early cultures of human malignant glioma exposed to 50 µg/ml (1,4-amino-2-methyl-5-pyrimidinyl)-methyl-3-(2-chloroethyl)-3-nitrosourea (ACNU), 50 µg/ml cisplatin, 1 µg/ml vincristine, or combinations of these chemotherapeutic agents. Primary chemoresistance was observed in 87% of tumors for ACNU, in 87% for cisplatin, and in 83% for vincristine. All tumors were examined for expression of multidrug-resistant p-glycoprotein, a transport protein of 170,000 D, by means of immunohistochemical staining with the JSB-1 antibody on paraffinized tumor sections. Eight of 15 specimens (53%) showed positive staining for the monoclonal antibody. Primary chemoresistance was overcome by addition of the calcium antagonists verapamil or nimodipine to the cultures if the original tumor expressed p-glycoprotein (p < 0.01 for verapamil, p < 0.05 for nimodipine). In tumors not expressing p-glycoprotein, addition of calcium antagonists to the cell cultures did not influence primary chemoresistance. It is concluded from these data that addition of calcium antagonists to the adjuvant chemotherapy of malignant gliomas might overcome primary chemoresistance in tumors expressing the multidrugresistant phenotype.

Abstract 1522: Predicting drug sensitivity based on gene array data for cytotoxic chemotherapeutic agents

2016 ◽  
Author(s):  
Joshua Mannheimer ◽  
Jared S. Fowles ◽  
Katherine Shaumberg ◽  
Dawn L. Duval ◽  
Ashok Prasad ◽  
...  
Keyword(s):  
Drug Sensitivity ◽  
Gene Array ◽  
Chemotherapeutic Agents ◽  
Array Data

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 Seizures and cancer: drug interactions of anticonvulsants with chemotherapeutic agents, tyrosine kinase inhibitors and glucocorticoids

2015 ◽  
Vol 3 (4) ◽  
pp. 245-260 ◽  
Author(s):  
Christa P. Bénit ◽  
Charles J. Vecht
Keyword(s):  
Drug Metabolism ◽  
Tyrosine Kinase ◽  
Drug Interactions ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Chemotherapeutic Agents ◽  
Cancer Drug ◽  
Large Individual ◽  
Pharmacokinetic Studies ◽  
Chemotherapeutic Drugs

Abstract Patients with cancer commonly experience seizures. Combined therapy with anticonvulsant drugs (AEDs) and chemotherapeutic drugs or tyrosine kinase inhibitors carries inherent risks on drug-drug interactions (DDIs). In this review, pharmacokinetic studies of AEDs with chemotherapeutic drugs, tyrosine kinase inhibitors, and glucocorticoids are discussed, including data on maximum tolerated dose, drug clearance, elimination half-life, and organ exposure. Enzyme-inducing AEDs (EIAEDs) cause about a 2-fold to 3-fold faster clearance of concurrent chemotherapeutic drugs metabolized along the same pathway, including cyclophosphamide, irinotecan, paclitaxel, and teniposide, and up to 4-fold faster clearance with the tyrosine kinase inhibitors crizotinib, dasatinib, imatinib, and lapatinib. The use of tyrosine kinase inhibitors, particularly imatinib and crizotinib, may lead to enzyme inhibition of concurrent therapy. Many of the newer generation AEDs do not induce or inhibit drug metabolism, but they can alter enzyme activity by other drugs including AEDs, chemotherapeutics and tyrosine kinase inhibitors. Glucocorticoids can both induce and undergo metabolic change. Quantitative data on changes in drug metabolism help to apply the appropriate dose regimens. Because the large individual variability in metabolic activity increases the risks for undertreatment and/or toxicity, we advocate routine plasma drug monitoring. There are insufficient data available on the effects of tyrosine kinase inhibitors on AED metabolism.

A Novel Multiparameter Flow Cytometric Cytotoxicity Assay Detects p53 Deletion as the Major Cause of In Vitro Resistance to Fludarabine in B-Cell Chronic Lymphocytic Leukemia.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4470-4470
Author(s):  
James Z. Huang ◽  
Antony C. Bakke ◽  
Guang Fan ◽  
Rita Braziel ◽  
Ken M. Gatter ◽  
...  
Keyword(s):  
Drug Sensitivity ◽  
Drug Exposure ◽  
Leukemic Cell ◽  
Chemotherapeutic Agents ◽  
Lymphocytic Leukemia ◽  
Leukemic Cells ◽  
Multiparameter Flow Cytometry ◽  
Diagnostic Strategy ◽  
Significant Difference

Abstract Individual patients with B-CLL demonstrate variable responses to standard induction and salvage therapeutic regimens. It would be highly desirable to develop a predictable and reproducible laboratory diagnostic strategy that guides the selection of appropriate drugs and/or regimens based on the drug sensitivity and resistance profiles of leukemic cells for individual patients. As a first step towards this goal, a study was designed to investigate the differences of in vitro drug sensitivity profiles of leukemic cells with different cytogenetic abnormalities from CLL patients. CLL cells from 43 patients were incubated in vitro with four commonly used chemotherapeutic agents (fludarabine, chlorambucil, cladribine or prednisolone) individually or in combination. Multiparameter flow cytometry was utilized to determine the decrease in leukemic cell viability after drug exposure. Both fresh and cryopreserved samples were assessed and were found to be equivalent for assay, regardless of the percentage of B-CLL cells or the degree of spontaneous apoptosis. The highest in vitro resistance to fludarabine, was seen in all seven cases of B-CLL cells with deletions of p53, a cytogenetic abnormality associated with poor clinical outcome. Interestingly, in vitro response to chlorambucil and prednisolone was seen some CLL cases with p53 deletion and correlated with clinical response to these drugs. In CLL cases without p53 deletion, a marked variability in vitro drug sensitivity CLL cells was observed but no significant difference was detected among cases with normal cytogenetics (n=13), ATM deletion (n=4), trisomy 12 (n=3), or 13q deletion (n=7). Our findings provide direct evidence of cellular resistance to fludarabine in CLL associated with p53 deletion, confirming prior clinical observations. In vitro drug sensitivity assay may prove useful in guiding choices for therapy for CLL patients based on the drug sensitivity profile of leukemic cells in individuals.

IL-6, IL-8 and VEGF Neutralisation Restores Drug Sensitivity to Conventional and Novel Treatment Combinations in a Multiple Myeloma Bone Marrow Micro-Environment Model.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2949-2949 ◽  
Author(s):  
Lenushka Maharaj ◽  
Rakesh Popat ◽  
John G Gribben ◽  
Simon Joel
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Cell Proliferation ◽  
Cell Viability ◽  
Stromal Cells ◽  
Direct Contact ◽  
Neutralizing Antibodies ◽  
Drug Sensitivity ◽  
Chemotherapeutic Agents ◽  
Humoral Factors

Abstract Abstract 2949 Stromal cells within the bone marrow microenvironment support the survival and proliferation of multiple myeloma (MM) cells, and confer resistance against chemotherapeutic agents. Although drug combinations (such as velcade and melphalan) are used to overcome such resistance; outcomes for myeloma patients remains sub-optimal. The microenvironment therefore represents a target to sensitise cells to chemotherapy. To further investigate this, we established a co-culture platform to culture CD138–positive MM cells and stromal cells directly or indirectly (separated by a 0.4μm micropore membrane). Co-culture with the human bone marrow stromal cell line (BMSC), HS-5, increased cell proliferation and cell viability of both MM cell lines (MMCLs) and 17 primary MM samples (Cell viability 53.6±11.2 (mean±s.d.) compared with 35.3±13.9 in media alone, (p<0.0001)). The stimulation of primary MM cell proliferation (p<0.01), confirmed the survival effects of BMSCs. Such antiapoptotic effects were markedly pronounced when the BMSCs were in direct contact with MM cells, however importantly conditioned media from BMSC cultures also demonstrated a significant increase in MM cell viability compared to control media alone (p<0.01). Exposure to standard chemotherapy (melphalan and dexamethasone) and novel therapies (bortezomib and the HDAC inhibitor UCL67022) resulted in a marked inhibition of MMCL and primary MM cell growth. However, these effects were attenuated when cells were either co-cultured in direct contact or in non-contact co-culture assays with HS-5 cells using transwell inserts. Such attenuation was accompanied by upregulation of cytokine-mediated STAT3 signaling, and PI3K/AKT, P38MAPK and ERK cell survival pathways within the MM cell. Cytokine profiling of supernatants from co-culture assays detected high levels of IL-6, IL-8, and VEGF. Levels of IL-8 correlated directly with resistance to velcade, and levels of both IL-8 and VEGF correlated with resistance to melphalan, whilst levels of IL-6 correlated with resistance to both agents in combination (Pearson's correlation coefficient p<0.05). Furthermore, neutralizing antibodies against these cytokines removed the protective effect conferred by the BMSC co-culture and restored drug sensitivity in primary MM cells. Combination of the IL-8 and VEGF antibodies gave an additive effect whereas all three antibodies in combination had the greatest sensitising effect. In conclusion, we demonstrate that humoral factors secreted by stromal cells protect MM cells from both standard, novel chemotherapy and the highly clinically active combination of velcade and melphalan. Whilst IL-6 neutralising antibodies are being evaluated in the clinic, this data provides compelling evidence towards the further evaluation of IL-8 and VEGF antibodies both alone and in combination. Disclosures: Gribben: Celgene: Honoraria; Roche: Honoraria; Pharmacyclics: Honoraria; GSK: Honoraria; Mundipharma: Honoraria; Gilead: Honoraria.

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