Simple Summary The tumor microenvironment (TME) is a complicated network, and several promising TME-targeted therapies, such as immunotherapy and targeted therapies, are now facing problems over low response rates and drug resistance. Vitamin C (VitC) has been extensively studied as a dietary nutrient and multi-targeted natural drug for fighting against tumor cells. The focus has been recently on its crucial functions in the TME. Here, we discuss the potential mechanisms of VitC in several specialized microenvironments, characterize the current status of its preclinical and clinical applications, and offer suggestions for future studies. This article is intended to provide basic researchers and clinicians with a detailed picture of VitC targeting the tumor microenvironment. Abstract Based on the enhanced knowledge on the tumor microenvironment (TME), a more comprehensive treatment landscape for targeting the TME has emerged. This microenvironment provides multiple therapeutic targets due to its diverse characteristics, leading to numerous TME-targeted strategies. With multifaced activities targeting tumors and the TME, vitamin C is renown as a promising candidate for combination therapy. In this review, we present new advances in how vitamin C reshapes the TME in the immune, hypoxic, metabolic, acidic, neurological, mechanical, and microbial dimensions. These findings will open new possibilities for multiple therapeutic avenues in the fight against cancer. We also review the available preclinical and clinical evidence of vitamin C combined with established therapies, highlighting vitamin C as an adjuvant that can be exploited for novel therapeutics. Finally, we discuss unresolved questions and directions that merit further investigation.

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Repurposing Vitamin C for Cancer Treatment: Focus on Targeting the Tumor Microenvironment

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer. HCC cells consume large amounts of glutamine to survive, but can adapt to glutamine depletion in the presence of an exogenous asparagine. L-asparaginase (ASNase) converts glutamine and asparagine to glutamate and aspartate, respectively, and has been used to treat leukemia. Here we examined the effects of ASNase treatment on HCC cells and explored the potential impact of combining ASNase with the tyrosine kinase inhibitor lenvatinib (Len) for HCC treatment. Cell viability and death of HCC cell lines treated with either Len or ASNase alone or with Len and ASNase combined were determined. We assessed mRNA and protein expression levels of glutamine synthetase (GS) and asparagine synthetase (ASNS) by real-time quantitative PCR and immunoblotting. The antitumor effect of the combination therapy relative to Len or ASNase monotherapy was also evaluated in a xenograft tumor mouse model. ASNase treatment inhibited growth of SNU387 and SNU398 HCC cells, which have low GS and high ASNS expression levels, respectively, but did not clearly inhibit growth of the other cell lines. Len plus ASNase combination therapy synergistically inhibited proliferation and induced oxidative stress leading to cell death of some HCC cells lines. However, cell death of Huh7 cells, which express ASCT2, an important glutamine transporter for cancer cells, was not affected by the combination treatment. In a xenograft model, Len combined with ASNase significantly attenuated tumor development relative to mice treated with Len or ASNase alone. ASNase-mediated targeting of two amino acids, glutamine and asparagine, which are indispensable for HCC survival, induces oxidative stress and can be a novel cancer treatment option that exerts a synergistic effect when used in combination with Len.

Enhanced Antitumor Effect in Liver Cancer by Amino Acid Depletion-Induced Oxidative Stress.

Introduction: Nutritional supplementation is an integral part of modern pharmacotherapeutic strategies for prostate diseases with different levels of evidence for specific nutrients.
 Provitamin A (beta-carotene), vitamin A (retinol) and prostate diseases. Their effects have not been sufficiently studied, and the available data are conflicting to recommend them as a nutritional supplement.
 Vitamin E (tocopherol) and prostate diseases. Its effects have not been sufficiently studied, and the available data are conflicting to recommend it as a nutritional supplement.
 Vitamin C (ascorbic acid) and prostate diseases. Its effects have not been sufficiently studied, and the available data are conflicted to recommend it as a nutritional supplement.
 Vitamin K and prostate diseases. Its effects have not been sufficiently studied, and the available data are conflicted to recommend it as a nutritional supplement.
 Vitamin D and prostate diseases. The evidence base of the vitamin D prostatotropic effects has been accumulated, which allows us to consider its deficiency replacement as an effective nutritional supplement in prostate diseases.
 Omega-3 PUFAs and prostate diseases. They have universal physiological effects; however, the evidence base for their recommendation as a nutritional supplement for prostate diseases is still insufficient.
 Zinc and prostate diseases. Positive effects of zinc on the prostate gland are known for a fact and allow us to recommend it as a nutritional supplement for prostate diseases.
 Selenium and prostate diseases. The reliably proven positive effects of selenium on the prostate gland allow us to recommend it as a nutritional supplement for prostate diseases.
 Magnesium and prostate diseases. Its effects have not been sufficiently studied, and the available data are conflicting to recommend it as a nutritional supplement.

Nutritional supplementation of the pharmacotherapy of prostate diseases

Cancer patients commonly present sarcopenia, myosteatosis, and systemic inflammation, which are risk factors of poor survival. In this study, sarcopenia and myosteatosis were defined from preoperative body computed tomography scans of 222 colorectal cancer (CRC) patients and analyzed in relation to tumor and patient characteristics, markers of systemic inflammation (modified Glasgow prognostic score (mGPS), neutrophil–lymphocyte ratio (NLR), serum levels of C-reactive protein (CRP), albumin, and 13 cytokines, and survival. Of the systemic inflammation markers, sarcopenia and/or myosteatosis associated with elevated NLR (p = 0.005) and low albumin levels (≤35 g/L) (p = 0.018), but not with mGPS or serum cytokine levels. In addition, myosteatosis was associated with a proximal tumor location (p = 0.039), serrated tumor subtype (p < 0.001), and severe comorbidities (p = 0.004). Multivariable analyses revealed that severe comorbidities and serrated histology were independent predictors of myosteatosis, and older age and elevated NLR were independent indicators of sarcopenia. Myosteatosis associated with shorter overall survival in univariable analysis (HR 1.959, 95% CI 1.24–3.10, p = 0.004) but not in multivariable analysis (p = 0.075). We conclude that sarcopenia and myosteatosis were associated with inflammatory marker NLR, but not with mGPS. Moreover, patients with serrated CRC may have an increased risk of myosteatosis. Myosteatosis or sarcopenia were not independent predictors of patient survival.

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Sarcopenia and Myosteatosis Are Associated with Neutrophil to Lymphocyte Ratio but Not Glasgow Prognostic Score in Colorectal Cancer Patients

In vitro and in vivo study on the treatment of non-small cell lung cancer with radionuclide labeled PD-L1 nanobody

Objective. To investigate the association between KRAS/NRAS/BRAF mutations and metabolic parameters of pretreatment 18F-FDG PET/CT in colorectal cancer (CRC). Methods. A total of 85 patients with CRC were included in the study. PET/CT was performed in all the patients before surgery. The histopathological examination and analysis of the gene mutational status of the primary tumor were conducted. The associations among clinical features, PET metabolic parameters, and the gene mutational status were investigated. Moreover, receiver operating characteristic (ROC) curves for maximum standard uptake value (SUVmax) of the primary tumor were generated along with analysis of the target tissue to nontarget tissue ratio (T/NT) for predicting the efficacy of KRAS/NRAS/BRAF mutations in CRC. Finally, the corresponding area under the curve, the optimal cutoff value, and the corresponding sensitivity and specificity were obtained. Results. The mutation rate of KRAS/NRAS/BRAF was 54.12% (46/85). In addition, both SUVmax and T/NT were significantly higher in the KRAS/NRAS/BRAF-mutation groups compared to the wild-type group (15.88 ± 6.71 vs. 12.59 ± 5.79, 8.04 ± 3.03 vs. 6.38 ± 2.80; and 0.004, respectively). Results from the ROC curve also showed that the cutoff values for T/NT and SUVmax were 5.14 and 12.40, respectively, while the predictive accuracy was 0.682 and 0.647, respectively. On the other hand, the sensitivity was 91.30% and 65.22% while the specificity was 43.59% and 64.10%, respectively. Moreover, univariate analysis showed that the KRAS/NRAS/BRAF mutation was not significantly associated with gender, age, lesion location, tumor length, pathological type, tissue differentiation, and UICC staging (all ). Conclusion. T/NT ratio and SUVmax could be the potential surrogate imaging indicators to predict the KRAS/NRAS/BRAF mutational status in CRC patients.

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Pretreatment 18F-FDG PET/CT Imaging Predicts the KRAS/NRAS/BRAF Gene Mutational Status in Colorectal Cancer.

Ascorbic acid analogue 6-Deoxy-6-[18F] fluoro-L-ascorbic acid as a tracer for identifying human colorectal cancer with SVCT2 overexpression.

Purpose: Glutamine synthetase (GS) is the only currently known enzyme responsible for synthesizing endogenous glutamine (Gln). GS exerts a critical role in the oncogenesis of endogenous Gln-dependent cancers, making it an attractive target for anti-tumor therapies. A mixed-function oxidation system consisting of vitamin C (VC), oxygen, and trace metals can oxidize GS and promote its degradation. The current study aims to explore the effect of pharmacological VC treatment on GS. Methods: Endogenous Gln-dependent cancer lines (breast cancer MCF7 and prostate cancer PC3) were selected to establish chronic Gln-deprived MCF7 and PC3 cell models. The expression of GS in parental and chronic Gln-deprived tumor cells exposed to VC treatment and control was determined by Western blot analysis. The anti-cancer effects of VC on parental and chronic Gln-deprived tumor cells were assessed by CCK-8 and annexin V-FITC/PI FACS assays. In addition, changes in cellular reactive oxygen species (ROS), glutathione (GSH) levels and NADPH/NADP + ratio were analyzed to explore the underlying mechanisms. Moreover, BALB/c nude mice xenografting with parental and chronic Gln-deprived prostate cancer cells were constructed to evaluate the in vivo therapeutic effect of VC. Finally, tumor 13N-ammonia uptake in mice bearing prostate cancer xenografts was analyzed following treatment with VC and the expression of GS in xenografts were detected by immunohistochemistry. Results: Cells overexpressing GS were obtained by chronic Gln deprivation. We found that the cytotoxic effect of VC on cancer cells was positively correlated with the expression of GS. Additionally, VC treatment led to a significant increase in ROS production, as well as GSH depletion and NADPH/NADP + reduction. These changes could be reversed by the antioxidant N-acetyl-L-cysteine (NAC). Furthermore, pharmacological VC treatment exhibited a more significant therapeutic effect on xenografts of prostate cancer cells overexpressing GS, that could be well monitored by 13N-ammonia PET/CT imaging. Conclusion: Our findings indicate that VC can kill cancer cells by targeting glutamine synthetase to induce oxidative stress. VC could be used as an anti-cancer treatment for endogenous glutamine-dependent cancers.

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Pharmacological Vitamin C Treatment Impedes the Growth of Endogenous Glutamine-Dependent Cancers by Targeting Glutamine Synthetase

Simple Summary High-dose vitamin C (VC) inhibits cell proliferation in a variety of tumors, which is mediated by ROS. Iron is an important factor in the Fenton reaction, in which H2O2 reacts with ferrous iron to produce hydroxyl radicals, which may enhance the killing of tumor cells. In this study, we investigated the roles of iron level and the mainly pathway of iron uptake-TF/TFR system on VC-induced cytotoxicity. We conducted a preliminary evaluation of the potential value of 68Ga-citrate imaging in the anti-tumor therapy of VC combined with iron supplementation. Abstract High-dose vitamin C (VC) exhibits anti-tumor effects, and the cytotoxicity of VC is correlated with oxidative stress. However, iron, as a redox metal, plays an important effect in redox cycling and free radical formation in cells. This study addresses the role of iron ion in the cytotoxicity of VC. We found that iron supplementation increases the anti-tumor effect of VC, which was influenced by the cellular iron uptake pathway–transferrin (TF)/transferrin receptor (TFR) system. The TFR expression of tumors can be assessed by 68Ga-citrate PET imaging, and it would be helpful to screen out the tumor type which is more sensitive to VC combined with an iron supplementation treatment.

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Role of Fe, Transferrin and Transferrin Receptor in Anti-Tumor Effect of Vitamin C

Abstract Purpose A series of radiotracers targeting fibroblast activation protein (FAP) with great pharmacokinetics have been developed for cancer diagnosis and therapy. Nevertheless, the use of dominant PET tracers, gallium-68–labeled FAPI derivatives, was limited by the short nuclide half-life and production scale, and the therapeutic tracers exhibited rapid clearance and insufficient tumor retention. In this study, we developed a FAP targeting ligand, LuFL, containing organosilicon-based fluoride acceptor (SiFA) and DOTAGA chelator, capable of labeling fluorine-18 and lutetium-177 in one molecular with simple and highly efficient labeling procedure, to achieve cancer theranostics. Methods The precursor LuFL ( 20 ) and [ nat Lu]Lu-LuFL ( 21 ) were successfully synthesized and labeled with fluorine-18 and lutetium-177 using a simple procedure. A series of cellular assays were performed to characterize the binding affinity and FAP specificity. PET imaging, SPECT imaging, and biodistribution studies were conducted to evaluate pharmacokinetics in HT-1080-FAP tumor-bearing nude mice. A comparison study of [ 177 Lu]Lu-LuFL ([ 177 Lu] 21 ) and [ 177 Lu]Lu-FAPI-04 was carried out in HT-1080-FAP xenografts to determine the cancer therapeutic efficacy. Results LuFL ( 20 ) and [ nat Lu]Lu-LuFL ( 21 ) demonstrated excellent binding affinity towards FAP (IC 50 : 2.29 ± 1.12 nM and 2.53 ± 1.87 nM), compared to that of FAPI-04 (IC 50 : 6.69 ± 0.88 nM). In vitro cellular studies showed that 18 F-/ 177 Lu-labeled 21 displayed high specific uptake and internalization in HT-1080-FAP cells. Micro-PET, SPECT imaging and biodistribution studies with [ 18 F]/[ 177 Lu] 21 revealed higher tumor uptake and longer tumor retention than those of [ 68 Ga]/[ 177 Lu]Ga/Lu-FAPI-04. The radionuclide therapy studies showed significantly greater inhibition of tumor growth for the [ 177 Lu] 21 group, than for the control group and the [ 177 Lu]Lu-FAPI-04 group. Conclusion The novel FAPI-based radiotracer containing SiFA and DOTAGA was developed as a theranostics radiopharmaceutical with simple and short labeling process, and showed promising properties including higher cellular uptake, better FAP binding affinity, higher tumor uptake and prolong retention compared to FAPI-04. Preliminary experiments with 18 F- and 177 Lu-labeled 21 showed promising tumor imaging properties and favorable anti-tumor efficacy. 

/pdf/a-radiohybrid-theranostics-ligand-labeled-with-fluorine-18-9o6oor2y.pdf

A radiohybrid theranostics ligand labeled with fluorine-18 and lutetium-177 for fibroblast activation protein-targeted imaging and radionuclide therapy

Jia Qiu

Papers

Pretreatment 18F-FDG PET/CT Imaging Predicts the KRAS/NRAS/BRAF Gene Mutational Status in Colorectal Cancer.

Ascorbic acid analogue 6-Deoxy-6-[18F] fluoro-L-ascorbic acid as a tracer for identifying human colorectal cancer with SVCT2 overexpression.

Pharmacological Vitamin C Treatment Impedes the Growth of Endogenous Glutamine-Dependent Cancers by Targeting Glutamine Synthetase

Role of Fe, Transferrin and Transferrin Receptor in Anti-Tumor Effect of Vitamin C

A radiohybrid theranostics ligand labeled with fluorine-18 and lutetium-177 for fibroblast activation protein-targeted imaging and radionuclide therapy