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A chirality-dependent action of vitamin C in suppressing Kirsten rat sarcoma mutant tumor growth by the oxidative combination: Rationale for cancer therapeutics.

ABSTRACT: Kirsten rat sarcoma (KRAS) mutant cancers, which constitute the vast majority of pancreatic tumors, are characterized by their resistance to established therapies and high mortality rates. Here, we developed a novel and extremely effective combinational therapeutic approach to target KRAS mutant tumors through the generation of a cytotoxic oxidative stress. At high concentrations, vitamin C (VC) is known to provoke oxidative stress and selectively kill KRAS mutant cancer cells, although its effects are limited when it is given as monotherapy. We found that the combination of VC and the oxidizing drug arsenic trioxide (ATO) is an effective therapeutic treatment modality. Remarkably, its efficiency is dependent on chirality of VC as its enantiomer d-optical isomer of VC (d-VC) is significantly more potent than the natural l-optical isomer of VC. Thus, our results demonstrate that the oxidizing combination of ATO and d-VC is a promising approach for the treatment of KRAS mutant human cancers.

SUBMITTER: Wu X

PROVIDER: S-EPMC7365556 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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A chirality-dependent action of vitamin C in suppressing Kirsten rat sarcoma mutant tumor growth by the oxidative combination: Rationale for cancer therapeutics.

Wu Xinggang X Park Mikyung M Sarbassova Dilara A DA Ying Haoqiang H Lee Min Gyu MG Bhattacharya Rajat R Ellis Lee L Peterson Christine B CB Hung Mien-Chie MC Lin Hui-Kuan HK Bersimbaev Rakhmetkazhi I RI Song Min Sup MS Sarbassov Dos D DD

International journal of cancer 20191008 10

Kirsten rat sarcoma (KRAS) mutant cancers, which constitute the vast majority of pancreatic tumors, are characterized by their resistance to established therapies and high mortality rates. Here, we developed a novel and extremely effective combinational therapeutic approach to target KRAS mutant tumors through the generation of a cytotoxic oxidative stress. At high concentrations, vitamin C (VC) is known to provoke oxidative stress and selectively kill KRAS mutant cancer cells, although its effe ...[more]

PMID: 31472018

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Project description:ObjectiveTo develop and validate radiomics models based on multiphasic CT in predicting Kirsten rat sarcoma virus (KRAS) gene mutation status in patients with colorectal cancer (CRC).Materials and methodsA total of 231 patients with pathologically confirmed CRC were retrospectively enrolled and randomly divided into training(n=184) and test groups(n=47) in a ratio of 4:1. A total of 1316 quantitative radiomics features were extracted from non-contrast phase (NCP), arterial-phase (AP) and venous-phase (VP) CT for each patient. Four steps were applied for feature selection including Spearman correlation analysis, variance threshold, least absolute contraction and selection operator, and multivariate stepwise regression analysis. Clinical and pathological characteristics were also assessed. Subsequently, three classification methods, logistic regression (LR), support vector machine (SVM) and random tree (RT) algorithm, were applied to develop seven groups of prediction models (NCP, AP, VP, AP+VP, AP+VP+NCP, AP&VP, AP&VP&NCP) for KRAS mutation prediction. The performance of these models was evaluated by receiver operating characteristics curve (ROC) analysis.ResultsAmong the three groups of single-phase models, the AP model, developed by LR algorithm, showed the best prediction performance with an AUC value of 0.811 (95% CI:0.685-0.938) in the test cohort. Compared with the single-phase models, the dual-phase (AP+VP) model with the LR algorithm showed better prediction performance (AUC=0.826, 95% CI:0.700-0.952). The performance of multiphasic (AP+VP+NCP) model with the LR algorithm (AUC=0.811, 95%CI: 0.679-0.944) is comparable to the model with the SVM algorithm (AUC=0.811, 95%CI: 0.695-0.918) in the test cohort, but the sensitivity, specificity, and accuracy of the multiphasic (AP+VP+NCP) model with the LR algorithm were 0.810, 0.808, 0.809 respectively, which were highest among these seven groups of prediction models in the test cohort.ConclusionThe CT radiomics models have the potential to predict KRAS mutation in patients with CRC; different phases may affect the predictive efficacy of radiomics model, of which arterial-phase CT is more informative. The combination of multiphasic CT images can further improve the performance of radiomics model.

Project description:BackgroundKirsten rat sarcoma (KRAS) mutation drives resistance to anti-epidermal growth factor receptor (anti-EGFR)-targeted therapies in rectal cancer. Amide proton transfer-weighted magnetic resonance imaging (APTw MRI) might be a supplement to the evaluation of KRAS mutation because the APTw value can reflect mobile cellular protein content in vivo. This study aimed to determine whether APTw MRI could predict KRAS mutation in rectal cancer and compare this technique with diffusion-weighted imaging (DWI).MethodsThis retrospective study reviewed 153 consecutive patients with rectal cancer from April 2019 to June 2021 in our hospital. Among them, a total of 55 patients who did not undergo neoadjuvant chemoradiotherapy and underwent preoperative APTw MRI, DWI, and postoperative KRAS tests were included in this study. In two-dimensional APTw images, two radiologists manually delineated three regions of interest (ROIs) along tumor contour in the largest slice and the adjacent two slices of tumor respectively. The mean APTw value within a ROI was calculated, and the values of three ROIs were averaged for each patient. In consecutive DWI images, two radiologists depicted the ROIs of the whole lesion, and the mean apparent diffusion coefficient (ADC) was generated. The intraclass correlation coefficient (ICC), Shapiro-Wilk test and Student's t-test were used for statistical analyses. Receiver operating characteristic (ROC) curves were constructed for APTw and ADC values respectively, and the area under the curve (AUC) was used to evaluate the diagnostic performance for the prediction of KRAS mutation.ResultsAmong these 55 patients, KRAS mutation occurred in 21 patients. The ICCs of two independent raters for APTw and ADC values were 0.937 [95% confidence interval (CI), 0.914-0.953] and 0.976 (95% CI, 0.959-0.986), respectively. ADC values did not show a statistically significant difference between the KRAS-mutant group and the wild type (WT) group (P=0.733). KRAS-mutant tumors exhibited a higher APTw value than WT tumors in patients with rectal non-mucinous adenocarcinoma (3.324%±0.685% vs. 2.230%±0.833%, P<0.001). The AUC of the APTw value was 0.827 (95% CI, 0.701-0.916), with a cutoff value of 2.4% (sensitivity, 95.2%; specificity, 55.9%).ConclusionsDWI cannot differentiate mutant KRAS genes from WT genes in patients with rectal cancer, but APTw MRI has potential for evaluating KRAS mutation in rectal cancer. The APTw value had moderate diagnostic performance in the prediction of KRAS mutation with a high sensitivity but a low specificity. APTw MRI might be a promising supplement to KRAS genomic analysis in rectal cancer patients.

Dataset Information

A chirality-dependent action of vitamin C in suppressing Kirsten rat sarcoma mutant tumor growth by the oxidative combination: Rationale for cancer therapeutics.

Publications

A chirality-dependent action of vitamin C in suppressing Kirsten rat sarcoma mutant tumor growth by the oxidative combination: Rationale for cancer therapeutics.

Similar Datasets

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