A single high-dose irradiation changes accumulation of methotrexate and gene expression levels of SLC and ABC transporters in cancer cells

Chemoradiotherapy is frequently used to treat cancer. Stereotactic body radiotherapy (SBRT) is a single high-dose radiotherapy used to treat a variety of cancers. The anticancer drug methotrexate (MTX) shows affinity for solute carrier (SLC) and ATP-binding cassette (ABC) transporters. This study investigated relationships between accumulation of methotrexate and gene expression levels of solute carrier and ATP-binding cassette transporters in cancer cells after a single and high-dose X-ray irradiation. Cancer cell lines were selected from lung and cervical cancer cell line that are commonly used for stereotactic body radiotherapy and effective with methotrexate. We examined expression levels of organic anion-transporting polypeptide (OATP)1B1, OATP1B3, OATP1B7, and organic anion transporter (OAT)1 as solute carrier transporters and multidrug resistance-associated protein (MRP)1 and MRP2 as ATP-binding cassette transporters, using real-time polymerase chain reaction and accumulation of 3H-MTX in cancer cells after 10-Gy irradiation, assuming stereotactic body radiotherapy. Cells were divided into three groups: Control without irradiation; 4 h after irradiation; and 24 h after irradiation. In control, gene expression levels of OAT1 in all cells was below the limit of measurement. After irradiation, gene expression levels of OATP1B1/1B3/1B7 showed changes in each cell line. Gene expression levels of MRP1/2 tended to increase after irradiation. Gene expression levels of OATP1B1/1B3/1B7 were much lower than those of MRP1/2. Accumulation of 3H-MTX tended to decrease over time after irradiation. Irradiation of cancer cells thus alters gene expression levels of both solute carrier transporters (OATP1B1/1B3/1B7) and ABC transporters (MRP1/2) and decreases accumulation of 3H-MTX in cancer cells over time due to elevated expression of MRP1/2.

[1]  P. Day,et al.  Cell Surface Transporters and Novel Drug Developments , 2022, Frontiers in Pharmacology.

[2]  A. Karlsson,et al.  Surface guided frameless positioning for lung stereotactic body radiation therapy , 2021, Journal of applied clinical medical physics.

[3]  H. Lei,et al.  Baicalein modulates the radiosensitivity of cervical cancer cells in vitro via miR-183 and the JAK2/STAT3 signaling pathway. , 2021, Advances in clinical and experimental medicine : official organ Wroclaw Medical University.

[4]  A. Ascolese,et al.  Stereotactic Body Radiation Therapy Boost in Patients With Cervical Cancer Ineligible for Brachytherapy. , 2021, Cancer diagnosis & prognosis.

[5]  U. Abacıoğlu,et al.  Stereotactic MR-guided online adaptive radiation therapy (SMART) for the treatment of liver metastases in oligometastatic patients: initial clinical experience , 2021, Radiation oncology journal.

[6]  Wei Wei,et al.  The effects of drug transporters on the efficacy of methotrexate in the treatment of rheumatoid arthritis. , 2021, Life sciences.

[7]  W. Yu,et al.  Polymeric Nanoscale Drug Carriers Mediate the Delivery of Methotrexate for Developing Therapeutic Interventions Against Cancer and Rheumatoid Arthritis , 2020, Frontiers in Oncology.

[8]  A. Meeson,et al.  Solute transporters and malignancy: establishing the role of uptake transporters in breast cancer and breast cancer metastasis , 2020, Cancer and Metastasis Reviews.

[9]  J. Thariat,et al.  Stereotactic radiation therapy for breast cancer in the elderly , 2020, Translational cancer research.

[10]  T. Yasugi,et al.  Determining the recommended dose of stereotactic body radiotherapy boost in patients with cervical cancer who are unsuitable for intracavitary brachytherapy: a phase I dose-escalation study. , 2019, Japanese journal of clinical oncology.

[11]  anonymous,et al.  Comprehensive review , 2019 .

[12]  E. Baldini,et al.  Neoadjuvant Chemotherapy, Concurrent Chemoradiation, and Adjuvant Chemotherapy for High-Risk Extremity Soft Tissue Sarcoma. , 2018, American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Annual Meeting.

[13]  Barton E Slatko,et al.  Overview of Next‐Generation Sequencing Technologies , 2018, Current protocols in molecular biology.

[14]  A. Swaminath,et al.  Stereotactic body radiation therapy (SBRT) in the management of non-small-cell lung cancer: Clinical impact and patient perspectives , 2018, Lung Cancer.

[15]  C. Kelsey,et al.  Surgery versus stereotactic body radiation therapy for stage I non–small cell lung cancer: A comprehensive review , 2018, Cancer.

[16]  M. Bredel,et al.  Fractionated stereotactic radiation therapy for intact brain metastases , 2017, Advances in radiation oncology.

[17]  T. Zhao,et al.  Effect of fractionated irradiation on the expression of multidrug resistance genes in the CNE1 human nasopharyngeal carcinoma cell line. , 2013, Molecular medicine reports.

[18]  T. Murakami,et al.  Involvement of Multiple Transporters-mediated Transports in Mizoribine and Methotrexate Pharmacokinetics , 2012, Pharmaceuticals.

[19]  I. Goldman,et al.  The antifolates. , 2012, Hematology/oncology clinics of North America.

[20]  T. Wiegel,et al.  Radiation- and Chemoinduced Multidrug Resistance in Colon Carcinoma Cells , 2009, Strahlentherapie und Onkologie.

[21]  T. Nakanishi.  Drug transporters as targets for cancer chemotherapy. , 2007, Cancer genomics & proteomics.

[22]  Robert D Timmerman,et al.  Stereotactic body radiation therapy. , 2004, Current problems in cancer.

[23]  D. Song,et al.  Stereotactic body radiation therapy. Rationale, techniques, applications, and optimization. , 2004, Oncology.

[24]  Peter J. Meier,et al.  Organic anion transporting polypeptides of the OATP/SLC21 family: phylogenetic classification as OATP/SLCO superfamily, new nomenclature and molecular/functional properties , 2004, Pflügers Archiv.

[25]  M. Davey,et al.  Fractionated irradiation of H69 small-cell lung cancer cells causes stable radiation and drug resistance with increased MRP1, MRP2, and topoisomerase IIalpha expression. , 2002, International journal of radiation oncology, biology, physics.

[26]  J. Smyth,et al.  Methotrexate in the chemotherapy of lung cancer. , 1981, Cancer treatment reports.

[27]  D. Ross,et al.  Low dose bleomycin and methotrexate in cervical cancer , 1976, Cancer.