Involvement of PD-L1-mediated Tumor Intrinsic Signaling and Immune Suppression in Tumorigenic Effect of α-Tocopherol

Zhenou Sun, Shutao Yin, Chong Zhao, Li Hong Fan, Hongbo Hu

Carcinogenesis . 2021 Oct 17;bgab096. doi: 10.1093/carcin/bgab096. Online ahead of print.

Abstract

Numerous studies have shown that the different isoforms vitamin E have distinct activity on carcinogenesis. α-Tocopherol (α-T), the most abundant vitamin E in certain types of food and animal tissues, has demonstrated a cancer-promoting effect in a number of human clinical trials and pre-clinical studies, whereas the γ- and δ- forms of Tocopherols and Tocotrienols have exhibited significant anticancer effect in various pre-clinical studies. However, the mechanisms underlying the tumorigenic effect of α-T have not yet been fully understood. In the present study, we found that α-T was able to activate Programmed death-ligand 1 (PD-L1)-mediated tumor-intrinsic signaling and immune suppression via JAK/STAT3-dependent transcriptional and ERK-dependent posttranscriptional mechanism. In line with PD-L1 induction, α-T treatment increased cancer cell viability in vitro and promoted tumor growth in LLC xenograft mouse model. The findings of the present study for the first time provided evidence that PD-L1-mediated tumor-intrinsic and immune escape mechanism contributed to the tumorigenic effect of α-T.

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δ-Tocotrienol sensitizes and re-sensitizes ovarian cancer cells to cisplatin via induction of G1 phase cell cycle arrest and ROS/MAPK-mediated apoptosis

Fabrizio Fontana, Monica Marzagalli, Michela Raimondi, Valentina Zuco, Nadia Zaffaroni, Patrizia Limonta

Cell Prolif . 2021 Sep 14;e13111. doi: 10.1111/cpr.13111. Online ahead of print.

Abstract

Objectives: Among gynaecologic malignancies, ovarian cancer (OC) represents the leading cause of death for women worldwide. Current OC treatment involves cytoreductive surgery followed by platinum-based chemotherapy, which is associated with severe side effects and development of drug resistance. Therefore, new therapeutic strategies are urgently needed. Herein, we evaluated the anti-tumour effects of Vitamin E-derived δ-tocotrienol (δ-TT) in two human OC cell lines, IGROV-1 and SKOV-3 cells.

Materials and methods: MTT and Trypan blue exclusion assays were used to assess δ-TT cytotoxicity, alone or in combination with other molecules. δ-TT effects on cell cycle, apoptosis, ROS generation and MAPK phosphorylation were investigated by flow cytometry, Western blot and immunofluorescence analyses. The synergism between δ-TT and chemotherapy was evaluated by isobologram analysis.

Results: We demonstrated that δ-TT could induce cell cycle block at G1-S phase and mitochondrial apoptosis in OC cell lines. In particular, we found that the proapoptotic activity of δ-TT correlated with mitochondrial ROS production and subsequent JNK and p38 activation. Finally, we observed that the compound was able to synergize with cisplatin, not only enhancing its cytotoxicity in IGROV-1 and SKOV-3 cells but also re-sensitizing IGROV-1/Pt1 cell line to its anti-tumour effects.

Conclusions: δ-TT triggers G1 phase cell cycle arrest and ROS/MAPK-mediated apoptosis in OC cells and sensitizes them to platinum treatment, thus representing an interesting option for novel chemopreventive/therapeutic strategies for OC.

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PEGylated phospholipid micelles containing D-α-tocopheryl succinate as multifunctional nanocarriers for enhancing the antitumor efficacy of doxorubicin

Weiwei Jiang, Qing Fan, Jing Wang, Bingning Zhang, Tangna Hao, Qixian Chen, Lei Li, Lixue Chen, Hongxia Cui, Zhen Li

Int J Pharm . 2021 Aug 6;120979. doi: 10.1016/j.ijpharm.2021.120979. Online ahead of print.

Abstract

The aim of this investigation is to clarify the effect of D-α-tocopheryl succinate (vitamin E succinate, VES) and distearoylphosphatidyl ethanolamine-poly(ethylene glycol) (DSPE-PEG) on the encapsulation and controlled release of doxorubicin (DOX) in nano-assemblies and their consequences on the anti-tumor efficacy of DOX. DOX molecules were successfully loaded into the hybrid micelles with VES and DSPE-PEG (VDPM) via thin-film hydration method, exhibiting a small hydrodynamic particle size (∼30 nm) and a weak negative zeta potential of around -5 mv. The obtained DOX-loaded VDPM2 displayed retarded DOX release at pH of 7.4, while substantially accelerated drug release at acidic pH of 5.0. Furthermore, the DOX-loaded VDPM2 exhibited substantially slower drug release rate at pH 7.4 compared with the drug-loaded VDPM1 or DPM preparation, benefiting for decreasing the premature DOX release during blood circulation. In vitro cell experiment indicated that DOX-Loaded micelles (DPM, VDPM1 and VDPM2) improved the cellular uptake of DOX in 4T1 and MDA-MB-231 cells. The existence of VES component in the structure of DOX-loaded micelles had no obvious influence on the subcellular distribution of the encapsulated DOX molecules. However, the DOX-loaded VDPM2 exhibited more pronounced cytotoxicity to 4T1 and MDA-MB-231 cancerous cells compared with DOX-loaded DPM and free DOX solution. The hybrid nanocarriers including VES and DSPE-PEG selectively induced intracellular ROS accumulation and increased level of cytoplasmic calcium ion in cancerous cells by interacting with mitochondria and endoplasmic reticulum, bringing about the improved cytotoxicity of DOX. In vivo antitumor efficacy investigation of DOX-loaded VDPM2 against 4T1 xenograft-bearing mice displayed satisfied therapeutic activity with negligible systemic toxicity, as evidenced by the histological analysis and change of body weight. The proposed DOX-loaded VDPM preparation, as a mulifunctional chemotherapeutic nanomedicine system, holds great potential and bright prospect for clinical tumor therapy.

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Vitamin E-facilitated carbon monoxide pro-drug nanomedicine for efficient light-responsive combination cancer therapy

Yaw Opoku-Damoah, Run Zhang, Hang T Ta, Zhi Ping Xu

Biomater Sci . 2021 Aug 4. doi: 10.1039/d1bm00941a. Online ahead of print.

Abstract

The quest to maximize therapeutic efficiency in cancer treatment requires innovative delivery nanoplatforms capable of employing different modules simultaneously. Combination therapy has proven to be one of the best anticancer strategies so far. Herein, we have developed a lipid-encapsulated nanoplatform that combines chemotherapy with photoresponsive gas therapy for colon cancer treatment. Carbon monoxide releasing molecules (CORMs) and vitamin E analogues (pure/pegylated α-tocopheryl succinate; α-TOS) were co-loaded into the lipid layer with core-shell upconversion nanoparticles (UCNPs), which converted 808 nm light to 360 nm photons to trigger CO release at the tumor site. This folic acid (FA)-targeting nanomedicine (Lipid/UCNP/CORM/α-TOS/FA: LUCTF) possessed a cancer-targeting ability and a light-triggered CO release ability for synergistic apoptosis of HCT116 cells via enhanced ROS generation and mitochondrial membrane breaking. In vivo data have confirmed the significantly enhanced therapeutic efficacy of LUCTF without any significant biosafety issues after intravenous administration. Thus, nanomedicine LUCTF represents a novel way for efficient cancer therapy via combining locally released CO and a compatible chemotherapeutic agent (e.g. α-TOS).

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Reduced infiltration of T-regulatory cells in tumours from mice fed daily with gamma-tocotrienol supplementation

Shonia Subramaniam, Jeya Seela Anandha Rao, Premdass Ramdas, Mei Han Ng, Methil Kannan Kutty, Kanga Rani Selvaduray, Ammu Kutty Radhakrishnan

Clin Exp Immunol . 2021 Jul 31. doi: 10.1111/cei.13650. Online ahead of print.

Abstract

Gamma-tocotrienol (γT3) is an analogue of vitamin E with beneficial effects on the immune system, including immune-modulatory properties. This study reports the immune-modulatory effects of daily supplementation of γT3 on host T-helper (Th) and T-regulatory (Treg) populations in a syngeneic mouse model of breast cancer. Female BALB/c mice were fed with either γT3 or vehicle (soy oil) for 2-weeks via oral gavage before they were inoculated with syngeneic 4T1 mouse mammary cancer cells (4T1 cells). Supplementation continued until the mice were sacrificed. Mice (n=6) were sacrificed at specified time-points for various analysis (blood leucocyte, cytokine production, and immunohistochemistry). Tumour volume was measured once every seven days. Gene expression studies were carried out on tumour-specific T-lymphocytes isolated from splenic cultures. Supplementation with γT3 increased CD4+ (p<0.05), CD8+ (p<0.05) T-cells and natural killer cells (p<0.05) but suppressed Treg cells (p<0.05) in peripheral blood when compared to animals fed with the vehicle. Higher interferon-gamma (IFNγ) and lower transforming growth factor-beta (TGF-ꞵ) levels were noted in the γT3 fed mice. Immunohistochemistry findings revealed higher infiltration of CD4+ cells, increased expression of interleukin-12 receptor-beta-2 (IL-12ꞵ2R), interleukin-24 (IL-24) and reduced expression of cells that express the forkhead box P3 (FoxP3) in tumours from the γT3 fed animals. Gene expression studies showed the downregulation of seven prominent genes in splenic CD4+ T-cells isolated from γT3-fed mice. Supplementation with γT3 from palm oil-induced T-cell dependent cell-mediated immune responses and suppressed Treg cells in the tumour microenvironment in a syngeneic mouse model of BC.

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Role of Vitamin E in Selected Malignant Neoplasms in Women

Anna Markowska, Michał Antoszczak, Janina Markowska, Adam Huczyński

Nutr Cancer . 2021 Jul 19;1-8. doi: 10.1080/01635581.2021.1952626. Online ahead of print.

Abstract

Vitamin E, which is actually a mixture of eight isoforms (four tocopherols and four tocotrienols), is a powerful antioxidant that protects polyunsaturated fatty acids against oxidation and has the ability to break the chain lipid peroxidation, which is used in the treatment of heart disease, atherosclerosis, muscle disorders or infertility among men. Studies in-vitro show that one of the effects of tocopherol is the reduction of cancer stem cell activity which is connected to poor clinical course. In the scientific literature, reports on the participation of vitamin E not only in protection against the mutagenic effects of reactive oxygen species, but also in its anti-angiogenic activity and the ability to inhibit the invasion and metastasis of neoplastic cells are increasingly common. In this context, the role of vitamin E in preventing the neoplastic process and selected malignant neoplasms among women seems to be of particular interest. In this article, we present the results of research on the potential anticancer effects of vitamin E in the fight against breast, cervical, endometrial and ovarian cancer.

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δ-Tocotrienol induces apoptosis and inhibits proliferation of nasopharyngeal carcinoma cells

Junjun Shen, Tao Yang, Yiping Tang, Tianyi Guo, Ting Guo, Tao Hu, Feijun Luo, Qinlu Lin

Food Funct . 2021 May 31. doi: 10.1039/d1fo00461a. Online ahead of print.

Abstract

Nasopharyngeal carcinoma has a notably high incidence rate in Southern China, Southeast Asia, North Africa, Middle East, and the Arctic. δ-Tocotrienol is abundant in cereal and has some health benefits. In our recent study, we showed that δ-tocotrienol exerted anti-inflammatory effects in murine macrophages in vitro. The aim of this study was to further investigate the chemopreventive effects of δ-tocotrienol on human CNE1 cells. We showed that δ-tocotrienol induced apoptosis and cell cycle arrest at G0/G1 and M phases in nasopharyngeal carcinoma cells. Microarray analysis revealed that after CNE1 cells were treated with δ-tocotrienol, 169 genes were up-regulated and 167 down-regulated. ERK1/2 was shown to play a vital role in cell cycle arrest by gene chips. The results suggest that δ-tocotrienol induces cell cycle arrest in CNE1 cells via the p16/CDK4/cyclin D1 signaling pathway. Western blots showed that CNE1 apoptosis was related to dysregulated expression of Bax-2 and Bcl-2. Furthermore, caspase-3, -8, -9 up-regulation was related to the apoptotic effect of δ-tocotrienol; therefore, δ-tocotrienol triggers apoptosis in CNE1 cells through caspase-3 signaling. δ-Tocotrienol may potentially be developed as an anti-cancer agent in the management of nasopharyngeal carcinoma.

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Risk of Colorectal Cancer in a Brazilian Population is Differentially Associated with the Intake of Processed Meat and Vitamin E

Radmila Raiani Alves Ribeiro, Isabella Rolim de Brito, Karolline Andrade Souza, Larissa de Castro Souza, Tiago Almeida de Oliveira, Mathias Weller

Nutr Cancer . 2021 May 17;1-10. doi: 10.1080/01635581.2021.1926519. Online ahead of print.

Abstract

The incidence and mortality rates of colorectal cancer (CRC) in Northeast Brazil are increasing. To study the association between CRC and diet, data were obtained from 64 patients with CRC and 123 sex- and age-matched controls. The dietary details were recorded using a validated food frequency questionnaire. Nutrient intake was calculated using Dietsys software (National Cancer Institute, Maryland, USA). In a binary logistic regression model of dietary components (model 1), the chance of CRC increased by 0.2% (odds ratio [OR] = 1.002; 95% confidence interval [CI]: 1.000-1.004) for each gram of processed meat intake per week (p < 0.010). Consumption of eggs decreased the chance by 0.1% per gram (OR = 0.999; 95% CI: 0.998-1.000; p < 0.050). The use of oil (including olive oil) for served food decreased the chance by 1.8% (OR = 0.982; 95% CI: 0.970-0.992) for each time consumed (p < 0.010). In a model of nutritional factors (model 2), intake of vitamin E decreased the chance by 16.8% (OR = 0.832; 95% CI: 0.725-0.940) for each milligram intake per week (p < 0.010). In model 1 and 2 smoking increased the chance of CRC by 10.294 (95%CI: 4.240-27.670) and 2.496 (95% CI: 1.425-3.566) times (p < 0.010; p < 0.010), respectively.

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Vitamin E succinate exerts anti-tumour effects on human cervical cancer cells via the CD47-SIRPɑ pathway both in vivo and in vitro

Xiaoli Huang, Markus Neckenig, Jintang Sun, Di Jia, Yu Dou, Dan Ai, Zhaodi Nan, Xun Qu

J Cancer . 2021 May 5;12(13):3877-3886. doi: 10.7150/jca.52315. eCollection 2021.

Abstract

Vitamin E succinate (RRR-a-tocopheryl succinate, VES) acts as a potent agent for cancer therapy and has no toxic and side effects on normal tissue cells. However, the mechanism by which VES mediates the effects are not yet fully understood. Here, we hypothesised that VES mediates antitumour activity on human cervical cancer cells via the CD47-SIRPɑ pathway in vivo and in vitro. Results indicated that the human cervical cancer HeLa cells treated with VES were more efficiently engulfed by THP-1-derived macrophages. In response to VES, the protein expression of CD47 on cell membranes and the mRNA level of CD47 in different human cervical cancer cells significantly decreased. And the level of calreticulin (CRT) mRNA in the VES-treated cells increased. By contrast, CRT protein expression was not altered. miRNA-155, miRNA-133 and miRNA-326 were up-regulated in the VES-treated HeLa cells. Knocking down miRNA-155 and miRNA-133 by RNA interference increased CD47 protein expression in the VES-treated cells. In vivo efficacy was determined in BALB/C nude mice with HeLa xenografts. Results showed that VES reduced tumour growth, increased overall survival and inhibited CD47 in the tumour transcriptionally and translationally. Furthermore, inflammatory factors (TNF-α, IL-12, IFN-γ, IL-2 and IL-10) in the spleen were altered because of VES treatment. Our results suggest that VES-induced antitumour activity is coupled to the CD47-SIRPɑ pathway in human cervical HeLa cancer cells.

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Antioxidant vitamins promote anticancer effects on low-concentration methotrexate-treated glioblastoma cells via enhancing the caspase-3 death pathway

Giou-Teng Yiang, Tsu-Yi Chen, Cian Chen, Yu-Ting Hung, Kuan-Chun Hsueh, Tsai-Kun Wu, Ying-Ru Pan, Yi-Chung Chien, Chao-Hsuan Chen, Yung-Lung Yu, Chyou-Wei Wei

Food Sci Nutr . 2021 May 1;9(6):3308-3316. doi: 10.1002/fsn3.2298. eCollection 2021 Jun.

Abstract

Vitamin C and vitamin E are well-known antioxidant vitamins, both of which are also applied as adjunct treatments for cancer therapy. Methotrexate (MTX) is a clinical drug that is used widely for rheumatoid arthritis and cancer treatment. Human glioblastoma multiforme (GBM) is an aggressive malignant brain tumor; the mean survival time for GBM patients is <2 years with traditional therapies. Developing and investigating novel treatments are important for clinical GBM therapy. Therefore, the aim of this study was to investigate whether combined treatment with vitamin C/E and MTX can display anticancer activities on GBM. Our studies showed that MTX displays anticancer effects on GBM in a dose-dependent manner, while vitamins C and E are not cytotoxic to glioblastoma. Importantly, this study showed that vitamins C and E can promote anticancer effects on low-concentration methotrexate-treated glioblastoma. Additionally, this study suggested that MTX alone or combined with vitamins C/E inhibits GBM cell growth via the caspase-3 death pathway.

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