Multidrug resistance (MDR), which is mediated by multiple drug efflux ATP-binding cassette (ABC) transporters, is a critical issue in the treatment of acute leukemia, with permeability glycoprotein (P-gp), multidrug resistance-associated protein 1, and breast cancer resistance protein (i.e., ABCG2) consistently being shown to be key effectors of MDR in cell line studies. Studies have demonstrated that intrinsic MDR can arise as a result of specific gene expression profiles and that drug-induced overexpression of P-gp and other MDR proteins can result in acquired resistance, with multiple ABC transporters having been shown to be overexpressed in cell lines selected for resistance to multiple drugs used to treat acute leukemia. Furthermore, numerous anticancer drugs, including agents commonly used for the treatment of acute leukemia (e.g., doxorubicin, vincristine, mitoxantrone, and methotrexate), have been shown to be P-gp substrates or to be susceptible to efflux mediated by other MDR proteins, and multiple clinical studies have demonstrated associations between P-gp or other MDR protein expression and responses to therapy or survival rates in acute leukemia. Here we review the importance of MDR in cancer, with a focus on acute leukemia, and we highlight the need for rapid accurate assessment of MDR status for optimal treatment selection. We also address the latest research on overcoming MDR, from inhibition of P-gp and other MDR proteins through various approaches (including direct antagonism and gene silencing) to the design of novel agents or novel delivery systems for existing therapeutic agents, to evade cellular efflux.

https://molpharm.aspetjournals.org/content/molpharm/early/2012/07/23/mol.112.079129.full.pdf

Drug Efflux Transporters and Multidrug Resistance in Acute Leukemia: Therapeutic Impact and Novel Approaches to Mediation

The key biologic pathways in cancer and the mechanisms of action of targeted anticancer agents are described; appearances of these agents at evaluation with a variety of clinically available imaging techniques are presented, with emphasis on use of functional and molecular imaging techniques to augment conventional assessment of tumor response.

Novel Oncologic Drugs: What They Do and How They Affect Images

// Shengwei Liu 1, * , Shuang Chen 1, * , Weiguang Yuan 2 , Hongyan Wang 3 , Kewang Chen 1 , Dianjun Li 1 and Dalin Li 4 1 Department of Immunology, Harbin Medical University and Heilongjiang Provincial Key Laboratory for Infection and Immunity, Harbin Medical University and Heilongjiang Academy of Medical Science, 150081, Harbin, China 2 Department of Cancer Immunology, Cancer Institute of Harbin Medical University, Department of Cancer Immunology, Heilongjiang Academy of Medical Sciences, 150081, Harbin, China 3 Institute of Harbin Hematology and Oncology, Harbin First Hospital, 150010, Harbin, China 4 Department of Breast Surgery, Harbin Medical University Cancer Hospital, 150081, Harbin, China * These authors contributed equally to this work and should be considered co-first authors Correspondence to: Dianjun Li, email: dianjunli@163.com Dalin Li, email: lidalin1975@163.com Keywords: PD-1/PD-L1, MDR1/P-gp, PI3K/AKT signaling, MAPK/ERK signaling, breast cancer Received: March 04, 2017      Accepted: September 24, 2017      Published: October 20, 2017 ABSTRACT Programmed cell death ligand 1 (PD-L1) is an immunosuppressive molecule expressed on tumor cells. By interacting with programmed cell death-1 (PD-1) on T cells, it inhibits immune responses. Because PD-L1 expression on cancer cells increases their chemoresistance, we investigated the correlation between PD-L1 and multidrug resistance 1/ P-glycoprotein (MDR1/P-gp) expression in breast cancer cells. Analysis of breast cancer tissues using tissue microarrays revealed a significant correlation between PD-L1 and MDR1/P-gp protein levels. Increased expression of PD-L1 was associated with lymph node metastasis and histological tumor grade. In addition, interaction of PD-L1 with PD-1 induced phosphorylation of AKT and ERK, resulting in the activation of PI3K/AKT and MAPK/ERK pathways and increased MDR1/P-gp expression in breast cancer cells. The PD-1/PD-L1 interaction also increased survival of breast cancer cells incubated with doxorubicin. These findings suggest that the PD-1/PD-L1 inhibition may increase chemotherapy efficacy by inhibiting the MDR1/P-gp expression in breast cancer cells.

/pdf/pd-1-pd-l1-interaction-up-regulates-mdr1-p-gp-expression-in-2uelcvo8gp.pdf

PD-1/PD-L1 interaction up-regulates MDR1/P-gp expression in breast cancer cells via PI3K/AKT and MAPK/ERK pathways.

Astragalus polysaccharides can regulate cytokine and P-glycoprotein expression in H22 tumor-bearing mice

Astragalus polysaccharides can regulate cytokine and P-glycoprotein expression in H22 tumor-bearing mice.

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death in Western countries. Despite novel molecular therapies, the majority of patients with advanced or metastatic disease show rapid progression and a median survival time of not more than 18 months. In the last decade, there has been increasing evidence that cancer stem cells (CSC) play a pivotal role in drug resistance, tumour regeneration and metastasis of various cancer entities including lung cancer. In this review, we discuss the evidence for stem cells in NSCLC, their predictive and prognostic significance, their specific mechanisms of resistance and potential targets and strategies for eradication of these cells. Consideration of the specific properties of CSC in lung cancer therapy might substantially contribute to increased response and prolonged survival rates in this disease.

Are we Missing the Target? – Cancer Stem Cells and Drug Resistance in Non-small Cell Lung Cancer

Primary intrinsic and/or acquired multidrug resistance (MDR) is the main obstacle to successful cancer treatment. Functional molecular imaging of MDR in cancer using single photon or positron emitters may be helpful to identify multidrug-resistant tumours and predict not only those patients who are resistant to treatment, with a clinically unfavourable prognosis, but also those who are susceptible to the development of drug toxicity or even certain tumours . Variations in the mdr1 gene product may directly affect the therapeutic effectiveness, and single nucleotide polymorphisms for the mdr1 gene may be associated with altered oral bioavailability of MDR1 substrates, drug resistance, and a susceptibility to some human diseases. The challenge of translating the concept of MDR modulation in vivo involves a complex cellular interplay between both malignant and normal cells. Integration and correlation of functional single photon emission tomography or positron emission tomography imaging findings with mdr1 genotype and clinical data may contribute to efficient management by selecting cancer patients with the appropriate molecular phenotype for maximal individual therapeutic benefit, as well as those who are non-responders. This review describes a role for functional imaging of classical mechanisms of MDR with an emphasis on readily available [(99m)Tc]MIBI scintigraphy. MIBI scintigraphy has been shown to be a non-invasive cost-effective in vivo assay of ATP-binding cassette transporters associated with MDR in cancer, including P-glycoprotein, multidrug-resistant protein 1 and breast cancer resistant protein. New imaging agents for molecular targets such as vascular endothelial growth factor and HER2 receptors, may potentially be combined with MDR imaging substrates to more accurately predict the therapeutic response to anticancer drugs, guiding individualised treatment while minimising the economic health costs of ineffective therapy in an era of personalised medicine

A M Peters

Papers

Imaging of multidrug resistance in cancer.