Resistance to radiation remains a significant clinical challenge in non-small cell lung carcinoma (NSCLC). It is therefore important to identify the underlying molecular and cellular features that drive acquired resistance. We generated genetically matched NSCLC cell lines to investigate characteristics of acquired resistance. Murine Lewis lung carcinoma (LLC) and human A549 cells acquired an approximate 1.5–2.5-fold increase in radiation resistance as compared to their parental match, which each had unique intrinsic radio-sensitivities. The radiation resistance (RR) was reflected in higher levels of DNA damage and repair marker γH2AX and reduced apoptosis induction after radiation. Morphologically, we found that radiation resistance A549 (A549-RR) cells exhibited a greater nucleus-to-cytosol (N/C) ratio as compared to its parental counterpart. Since the N/C ratio is linked to the differentiation state, we next investigated the epithelial-to-mesenchymal transition (EMT) phenotype and cellular plasticity. We found that A549 cells had a greater radiation-induced plasticity, as measured by E-cadherin, vimentin and double-positive (DP) modulation, as compared to LLC. Additionally, migration was suppressed in A549-RR cells, as compared to A549 cells. Subsequently, we confirmed in vivo that the LLC-RR and A549-RR cells are also more resistance to radiation than their isogenic-matched counterpart. Moreover, we found that the acquired radiation resistance also induced resistance to cisplatin, but not carboplatin or oxaliplatin. This cross-resistance was attributed to induced elevation of thiol levels. Gamma-glutamylcysteine synthetase inhibitor buthionine sulfoximine (BSO) sensitized the resistant cells to cisplatin by decreasing the amount of thiols to levels prior to obtaining acquired radiation resistance. By generating radiation-resistance genetically matched NSCLC we were able to identify and overcome cisplatin cross-resistance. This is an important finding arguing for combinatorial treatment regimens including glutathione pathway disruptors in patients with the potential of improving clinical outcomes in the future.
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Research Article|
December 11 2023
Acquired Radiation Resistance Induces Thiol-dependent Cisplatin Cross-resistance
Samir V. Jenkins;
Samir V. Jenkins
aDepartment of Radiation Oncology and
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Shruti Shah;
Shruti Shah
aDepartment of Radiation Oncology and
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Azemat Jamshidi-Parsian;
Azemat Jamshidi-Parsian
aDepartment of Radiation Oncology and
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Amir Mortazavi;
Amir Mortazavi
aDepartment of Radiation Oncology and
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Hailey Kristian;
Hailey Kristian
aDepartment of Radiation Oncology and
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Gunnar Boysen;
Gunnar Boysen
bEnvironment Health Sciences, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205
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Kieng B. Vang;
Kieng B. Vang
aDepartment of Radiation Oncology and
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Robert J. Griffin;
Robert J. Griffin
aDepartment of Radiation Oncology and
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Narasimhan Rajaram;
Narasimhan Rajaram
cDepartment for Biomedical Engineering, University of Arkansas, University of Arkansas at Fayetteville, Fayetteville, Arkansas 72701
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Ruud P.M. Dings
Ruud P.M. Dings
1
aDepartment of Radiation Oncology and
1Corresponding author: Ruud P.M. Dings, 4301 W. Markham, Mail Slot #771, Little Rock, AR 72205; email: [email protected].
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Radiat Res (2023)
Article history
Received:
January 06 2023
Accepted:
November 22 2023
Citation
Samir V. Jenkins, Shruti Shah, Azemat Jamshidi-Parsian, Amir Mortazavi, Hailey Kristian, Gunnar Boysen, Kieng B. Vang, Robert J. Griffin, Narasimhan Rajaram, Ruud P.M. Dings; Acquired Radiation Resistance Induces Thiol-dependent Cisplatin Cross-resistance. Radiat Res 2023; doi: https://doi.org/10.1667/RADE-23-0005.1
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