Drug resistance: The clinical problem

Elucidating the expression and function of Numbl during cell adhesion-mediated drug resistance (CAM-DR) in multiple myeloma (MM)

BMC Cancer ◽

10.1186/s12885-019-6446-y ◽

2019 ◽

Vol 19 (1) ◽

Cited By ~ 1

Author(s):

Yuejiao Huang ◽

Xianting Huang ◽

Chun Cheng ◽

Xiaohong Xu ◽

Hong Liu ◽

...

Keyword(s):

Cell Cycle ◽

Multiple Myeloma ◽

Drug Resistance ◽

Cell Adhesion ◽

Cell Lines ◽

Molecular Mechanisms ◽

Clinical Problem ◽

Integrin Β1 ◽

Cell Viability Assay ◽

Adhesion Model

Abstract Background Cell adhesion-mediated drug resistance (CAM-DR) is a major clinical problem that prevents successful treatment of multiple myeloma (MM). In particular, the expression levels of integrin β1 and its sub-cellular distribution (internalization and trafficking) are strongly associated with CAM-DR development. Methods Development of an adhesion model of established MM cell lines and detection of Numbl and Integrinβ1 expression by Western Blot analysis. The interaction between Numbl and Integrinβ1 was assessed by a co-immunoprecipitation (CO-IP) method. Calcein AM assay was performed to investigate the levels of cell adhesion. Finally, the extent of CAM-DR in myeloma cells was measured using cell viability assay and flow cytometry analysis. Results Our preliminary date suggest that Numbl is differentially expressed in a cell adhesion model of MM cell lines. In addition to binding to the phosphotyrosine-binding (PTB) domain, the carboxyl terminal of Numbl can also interact with integrin β1 to regulate the cell cycle by activating the pro-survival PI3K/AKT signaling pathway. This study intends to verify and elucidate the interaction between Numbl and integrin β1 and its functional outcome on CAM-DR. We have designed and developed a CAM-DR model using MM cells coated with either fibronectin or bone marrow stromal cells. We assessed whether Numbl influences cell-cycle progression and whether it, in turn, contributes to activation of PI3K/AKT signal pathway through the adjustment of its carboxyl end. Finally, we showed that the interaction of Numbl with integrin β1 promotes the formation of CAM-DR in MM cells. Conclusions Our findings elucidated the specific molecular mechanisms of CAM-DR induction and confirmed that Numbl is crucial for the development of CAM-DR in MM cells.

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Drug Resistance and Biofilm Production among Pseudomonas aeruginosa Clinical Isolates in a Tertiary Care Hospital of Nepal

Nepal Medical College Journal ◽

10.3126/nmcj.v21i2.25109 ◽

2019 ◽

Vol 21 (2) ◽

pp. 110-116

Author(s):

Rajani Shrestha ◽

N. Nayak ◽

D.R. Bhatta ◽

D. Hamal ◽

S.H. Subramanya ◽

...

Keyword(s):

Pseudomonas Aeruginosa ◽

Drug Resistance ◽

Biofilm Formation ◽

Tertiary Care ◽

Clinical Problem ◽

Multidrug Resistant ◽

Clinical Isolates ◽

Diffusion Method ◽

Care Hospital ◽

Microbiological Methods

Clinical isolates of Pseudomonas aeruginosa often exhibit multidrug resistance due to their inherent ability to form biofilms. Drug resistance in Ps. aeruginosa is a major clinical problem, especially in the management of patients with nosocomial infections and those admitted to ICUs with indwelling medical devices. To evaluate the biofilm forming abilities of the clinical isolates of Ps. aeruginosa and to correlate biofilm formation with antibiotic resistance. A total of 90 consecutive isolates of Ps. aeruginosa obtained from various specimens collected from patients visiting the Manipal Teaching Hospital, Pokhara, Nepal between January 2018 - October 2018 were studied. Isolates were identified by standard microbiological methods. Antibiotic susceptibility testing was performed by Kirby-Bauer disc diffusion method. All the isolates were tested for their biofilm forming abilities by employing the tissue culture plate assay. Of the 90 Ps. aeruginosa isolates, maximum i.e 42 (46.6%) were from patients in the age group of > 50 years. Majority (30; 33.3%) of the isolates were obtained from sputum samples. However, percentage isolation from other specimens like urine, endotracheal tube (ETT), pus, eye specimens and blood were 18.9%, 16.7%, 16.7%, 7.8% and 6.7% respectively. All the isolates were sensitive to polymixin B and colistin, 91.1% of the organisms were sensitive to imipenem, and more than 80% to aminoglycosides (80% to gentamicin, 83.3% to amikacin). A total of 29 (32.2%) organisms were biofilm producers. Maximum numbers of biofilm producing strains were obtained from ETT (8 of 15; 53.3%), pus (8 of 15; 53.3%) and blood (2 of 6; 33.3%) i.e from all invasive sites. None of the isolates from noninvasive specimens such as conjunctival swabs were biofilm positive. Significantly higher numbers of biofilm producers (23 of 29; 79.3%) were found to be multidrug resistant as compared to non-biofilm (6 of 61; 9.8%) producers (p=0.000). Ps. aeruginosa colonization leading to biofilm formation in deep seated tissues and on indwelling devices is a therapeutic challenge as majority of the isolates would be recalcitrant to commonly used antipseudomonal drugs. Effective monitoring of drug resistance patterns in all Pseudomonas clinical isolates should be a prerequisite for successful patient management.

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Paclitaxel in breast cancer – drug resistance and strategies to counteract it

Postępy Higieny i Medycyny Doświadczalnej ◽

10.5604/01.3001.0013.5251 ◽

2019 ◽

Vol 73 ◽

pp. 508-515 ◽

Cited By ~ 1

Author(s):

Alicja Zajdel ◽

Daniel Wolny ◽

Magdalena Kałucka-Janik ◽

Adam Wilczok

Keyword(s):

Breast Cancer ◽

Drug Resistance ◽

Cancer Cells ◽

Cancer Biology ◽

Breast Cancer Cells ◽

Metastatic Breast ◽

Clinical Problem ◽

Tumour Cells ◽

Cancer Drug ◽

Acquired Drug Resistance

Despite significant progress in the last few decades in breast cancer biology and the use of different therapeutic strategies, this cancer remains a serious clinical problem. Paclitaxel (PTX) is used to treat breast cancer both as a monotherapy and in combination with other anticancer drugs depending on the severity of the cancer, the presence of metastases and previous therapeutic management. It is characterized by high effectiveness both in early breast cancer and in metastatic breast cancer. Primary or acquired drug resistance of tumour cells to taxanes is a significant clinical problem in the treatment of various histological types of breast cancer. The main problem of resistance of tumour cells is the complexity and multifactorial nature of this phenomenon, which is conditioned by numerous different mechanisms that interact with each other. Among the known mechanisms of breast cancer cells resistance to PTX, the most important are the active removal of the drug from the cell related to the increased activity of ABC family membrane transporters, enhanced drug detoxification by cytochrome P450, CYP3A4/5 and CYP2C8 enzymes, changes within the molecular targets of PTX, microtubule and disorders of microtubule associated protein (MAPs) or apoptosis. This paper presents the latest reports on the mechanisms of drug resistance of breast cancer cells to PTX, pointing to modern strategies to counteract this adverse phenomenon.

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What does not kill a tumour may make it stronger:in silicoInsights into Chemotherapeutic Drug Resistance

10.1101/230318 ◽

2017 ◽

Author(s):

Sara Hamis ◽

Perumal Nithiarasu ◽

Gibin G Powathil

Keyword(s):

Drug Resistance ◽

Cancer Cell ◽

In Silico ◽

Treatment Strategies ◽

Study Drug ◽

Clinical Problem ◽

Drug Resistant ◽

Chemotherapeutic Drug ◽

Chemotherapy Treatment ◽

Drug Induced

AbstractTumour recurrence post chemotherapy is an established clinical problem and many cancer types are often observed to be increasingly drug resistant subsequent to chemotherapy treatments. Drug resistance in cancer is a multipart phenomenon which can be derived from several origins and in many cases it has been observed that cancer cells have the ability to possess, acquire and communicate drug resistant traits.Here, anin silicoframework is developed in order to study drug resistance and drug response in cancer cell populations exhibiting various drug resistant features. The framework is based on an on-lattice hybrid multiscale mathematical model and is equipped to simulate multiple mechanisms on different scales that contribute towards chemotherapeutic drug resistance in cancer. This study demonstrates how drug resistant tumour features may depend on the interplay amongst intracellular, extracelluar and intercellular factors. On a cellular level, drug resistant cell phenotypes are here derived from inheritance or mutations that are spontaneous, drug-induced or communicated via exosomes. Furthermore intratumoural heterogeneity and spatio-temporal drug dynamics heavily influences drug delivery and the development of drug resistant cancer cell subpopulations. Chemotherapy treatment strategies are here optimised for variousin silicotumour scenarios and treatment objectives. We demonstrate that optimal chemotherapy treatment strategies drastically depend on which drug resistant mechanisms are activated, and that furthermore suboptimal chemotherapy administration may promote drug resistance.

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Mutations of Helicobacter pylori RdxA are mainly related to the phylogenetic origin of the strain and not to metronidazole resistance

Journal of Antimicrobial Chemotherapy ◽

10.1093/jac/dkaa302 ◽

2020 ◽

Vol 75 (11) ◽

pp. 3152-3155

Author(s):

Shuzhen Zhang ◽

Xiangyu Wang ◽

Michael J Wise ◽

Yongsheng He ◽

Haiting Chen ◽

...

Keyword(s):

Drug Resistance ◽

Helicobacter Pylori ◽

Phylogenetic Analyses ◽

Clinical Problem ◽

23S Rrna ◽

Rrna Gene ◽

Metronidazole Resistance ◽

Resistant Strains ◽

H Pylori ◽

Technology Mutation

Abstract Objectives Drug resistance of Helicobacter pylori is a major clinical problem worldwide. The objective of the present study was to investigate the prevalence of antibiotic-resistant H. pylori in the city of Shenzhen in China, as well as to identify the genetic mutations specifically associated with drug resistance rather than unrelated phylogenetic signals. Methods Antibiotic susceptibility testing was performed on 238 clinical strains successfully isolated from H. pylori-positive dyspeptic patients who underwent gastroscopy at the Department of Gastroenterology in Shenzhen People’s Second Hospital. Following WGS of all strains using Illumina technology, mutation and phylogenetic analyses were performed. Results The resistance rates were 84.9%, 35.3%, 25.2% and 2.1% for metronidazole, clarithromycin, ciprofloxacin and rifampicin, respectively. An A2143G conversion in the 23S rRNA gene was the primary mutation observed in clarithromycin-resistant strains, whilst N87K/I and D91G/N/Y in GyrA were detected in ciprofloxacin-resistant strains. In RdxA, our results demonstrated that only R16H/C and M21A are significant contributors to metronidazole resistance; there were 15 other sites, but these are phylogenetically related and thus unrelated to metronidazole resistance. Conclusions There is a high prevalence of metronidazole, clarithromycin and ciprofloxacin resistance and a low prevalence of rifampicin resistance in H. pylori from Shenzhen, China. Omission of phylogenetically related sites will help to improve identification of sites genuinely related to antibiotic resistance in H. pylori and, we believe, other species.

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Gene Expression Signature of Acquired Chemoresistance in Neuroblastoma Cells

International Journal of Molecular Sciences ◽

10.3390/ijms21186811 ◽

2020 ◽

Vol 21 (18) ◽

pp. 6811

Author(s):

Mohamed Jemaà ◽

Wondossen Sime ◽

Yasmin Abassi ◽

Vito Lasorsa ◽

Julie Bonne Køhler ◽

...

Keyword(s):

Gene Expression ◽

Drug Resistance ◽

Expression Profiles ◽

Expression Patterns ◽

Neuroblastoma Cells ◽

Gene Expression Signature ◽

Clinical Problem ◽

Cancer Drug ◽

Specific Gene ◽

Response To Chemotherapy

Drug resistance of childhood cancer neuroblastoma is a serious clinical problem. Patients with relapsed disease have a poor prognosis despite intense treatment. In the present study, we aimed to identify chemoresistance gene expression signatures in vincristine resistant neuroblastoma cells. We found that vincristine-resistant neuroblastoma cells formed larger clones and survived under reduced serum conditions as compared with non-resistant parental cells. To identify the possible mechanisms underlying vincristine resistance in neuroblastoma cells, we investigated the expression profiles of genes known to be involved in cancer drug resistance. This specific gene expression patterns could predict the behavior of a tumor in response to chemotherapy and for predicting the prognosis of high-risk neuroblastoma patients. Our signature could help chemoresistant neuroblastoma patients in avoiding useless and harmful chemotherapy cycles.

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