Targeting Lactate Dehydrogenase A Improves Radiotherapy Efficacy in Non-Small Cell Lung Cancer: From Bedside to Bench

Yang, Yunjun; Chong, Yu; Dai, Wu; Xia, Zhou; Ji, Yanjun; Qiu, Guangle; Du, Xianghui

doi:10.21203/rs.3.rs-222733/v1

Cited by 3 publications

(2 citation statements)

References 48 publications

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“…Our previous study [26] has revealed that oxamate, an inhibitor of LDH-A, signi cantly suppressed the proliferation of NSCLC cells, while it exerted a much lower toxicity in normal cells. LDH-A inhibition resulted in ATP reduction and ROS (reactive oxygen species) burst in cancer cells, which lead to apoptosis and G2/M arrest and increase radiosensitivity in NSCLC cells [27].…”

Section: Discussionmentioning

confidence: 99%

Serum lactate dehydrogenase predicts brain metastasis and survival in limited stage small-cell lung cancer patients treated with thoracic radiotherapy and prophylactic cranial irradiation

Liu

Shen

et al. 2022

Preprint

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Background: Small cell lung cancer (SCLC) is characterized with high risk of brain metastasis and poor survival. This study aimed to assess the prognostic role of LDH in limited stage small-cell lung cancer (LS-SCLC) treated with thoracic radiotherapy (TRT) and prophylactic cranial irradiation (PCI).Methods: This study retrospectively evaluated 197 consecutive patients who underwent TRT and PCI for LS-SCLC between November 2005 and October 2017. Both pretreatment and maximal serum LDH levels (mLDH) during treatment were checked, increased LDH level was defined as more than 240 IU/ml .Clinical factors were tested for associations with intracranial progression-free survival (IPFS) and overall survival (OS) after PCI. The Kaplan–Meier method was used to calculate survival rates, and multivariate Cox regression analyses were carried out to identify variables associated with survival.Results: Of the total patients, 95 had higher pretreatment LDH levels, and serum LDH levels were increased in 95 patients during treatment. In patients with the normal and elevated mLDH groups, the 1-, 2- and 5-year IPFS rate were 96.7% vs. 90.1%,91.7% vs. 73.8% and 87.8% vs. 61.0% (P < 0.01),respectively. Compared to those with normal LDH level, patients with increased mLDH level had higher cumulative risk of intracranial metastasis [hazard ratio (HR),3.87; 95% confidence interval (CI), 1.73-8.63; P< 0.01], and worse overall survival [HR,2.59; 95% CI, 1.67-4.04; P < 0.01]. The factors of LDH level at baseline or changes between pretreatment level and maximum level during treatment failed to predict BMs or OS with statistical significance.In the multivariate analyses, both mLDH during treatment [HR,3.53; 95% CI, 1.57-7.92; P = 0.002] and age≥60 [HR, 2.46; 95% CI,1.22-4.94; P =0.012] were independently associated with worse IPFS. Factors significantly associated with worse OS included mLDH during treatment [HR, 2.45; 95% CI, 1.56-3.86; P< 0.001], IIIB stage [HR, 1.75; 95% CI,1.06-2.88; P =0.029] and conventional radiotherapy applied in TRT [HR, 1.66; 95% CI,1.04-2.65; P =0.034]. Conclusion: mLDH level during treatment, but not pretreatment level predicts brain metastasis and survival in LS-SCLC patients treated with TRT and PCI, which may provide valuable information for identifying patients with poor survival outcomes.

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Section: Discussionmentioning

confidence: 99%

Serum lactate dehydrogenase predicts brain metastasis and survival in limited stage small-cell lung cancer patients treated with thoracic radiotherapy and prophylactic cranial irradiation

Liu

Shen

et al. 2022

Preprint

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“…The sensitivity of tumor cells to radiation defines the efficacy of radiotherapy. Nevertheless, a growing number of studies have indicated that patients with NSCLC can acquire resistance to radiotherapy, which limits the effects of radiotherapy (5)(6)(7). Therefore, it is crucial to explore the underlying mechanism of radioresistance in NSCLC.…”

Section: Introductionmentioning

confidence: 99%

miR‑148a promotes cell sensitivity through downregulating SOS2 in radiation‑resistant non‑small cell lung cancer cells

Zhang

2022

Oncol Lett

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Non-small cell lung carcinoma (NSCLC) is the most common type of lung cancer; however, radioresistance is a significant barrier in NSCLC radiotherapy. MicroRNA (miR)-148a has been reported to be a tumor suppressor in various types of cancer, including NSCLC. In the present study, the potential role of miR-148a in regulating radiosensitivity of NSCLC cells was investigated. Serum miR-148a expression was evaluated by reverse transcription-quantitative PCR in patients with NSCLC and healthy controls. The effects of miR-148a on cell viability, migration and invasion were assessed by Cell Counting Kit-8 and Transwell assays in radiation-resistant NSCLC cells. Serum miR-148a was downregulated in patients with NSCLC compared with healthy controls and its expression was significantly increased after radiotherapy. By contrast, miR-148a expression was decreased in the radioresistant patients compared with the radiosensitivity patients. Additionally, miR-148a overexpression inhibited the cell proliferation, migration and invasion of radiation-resistant NSCLC cells. In addition, miR-148a had putative binding site with Son of Sevenless 2 (SOS2) and negatively regulated SOS2 expression. Silencing SOS2 expression significantly suppressed miR-148a inhibitor-induced increase in radiosensitivity in NSCLC. In conclusion, the results of the present study suggested that miR-148a could enhance the radiosensitivity of NSCLC cells through targeting SOS2, thus providing potential therapeutic targets to improve radiotherapy in NSCLC.

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Lactate metabolic pathway regulates tumor cell metastasis and its use as a new therapeutic target

Xing,

Li,

Zhou

et al. 2023

Exploration of Medicine

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Abnormal energy metabolism is one of the ten hallmarks of tumors, and tumor cell metabolism provides energy and a suitable microenvironment for tumorigenesis and metastasis. Tumor cells can consume large amounts of glucose and produce large amounts of lactate through glycolysis even in the presence of oxygen, a process called aerobic glycolysis, also known as the Warburg effect. Lactate is the end product of the aerobic glycolysis. Lactate dehydrogenase A (LDHA), which is highly expressed in cancer cells, promotes lactate production and transports lactate to the tumor microenvironment and is taken up by surrounding stromal cells under the action of monocarboxylate transporter 1/4 (MCT1/4), which in turn influences the immune response and enhances the invasion and metastasis of cancer cells. Therapeutic strategies targeting lactate metabolism have been intensively investigated, focusing on its metastasis-promoting properties and various target inhibitors; AZD3965, an MCT1 inhibitor, has entered phase I clinical trials, and the LDHA inhibitor N-hydroxyindole (NHI) has shown cancer therapeutic activity in pre-clinical studies. Interventions targeting lactate metabolism are emerging as a promising option for cancer therapy, with chemotherapy or radiotherapy combined with lactate-metabolism-targeted drugs adding to the effectiveness of cancer treatment. Based on current research, this article outlines the role of lactate metabolism in tumor metastasis and the potential value of inhibitors targeting lactate metabolism in cancer therapy.

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Targeting Lactate Dehydrogenase A Improves Radiotherapy Efficacy in Non-Small Cell Lung Cancer: From Bedside to Bench

Cited by 3 publications

References 48 publications

Serum lactate dehydrogenase predicts brain metastasis and survival in limited stage small-cell lung cancer patients treated with thoracic radiotherapy and prophylactic cranial irradiation

Serum lactate dehydrogenase predicts brain metastasis and survival in limited stage small-cell lung cancer patients treated with thoracic radiotherapy and prophylactic cranial irradiation

miR‑148a promotes cell sensitivity through downregulating SOS2 in radiation‑resistant non‑small cell lung cancer cells

Lactate metabolic pathway regulates tumor cell metastasis and its use as a new therapeutic target

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