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15 pages, 2067 KiB

Open AccessArticle

Dichloroacetate and Quercetin Prevent Cell Proliferation, Induce Cell Death and Slow Tumor Growth in a Mouse Model of HPV-Positive Head and Neck Cancer

by Yongxian Zhuang, Joseph D. Coppock, Allison B. Haugrud, John H. Lee, Shanta M. Messerli and W. Keith Miskimins

Cancers 2024, 16(8), 1525; https://doi.org/10.3390/cancers16081525 - 17 Apr 2024

Viewed by 289

Abstract

Elevated glucose uptake and production of lactate are common features of cancer cells. Among many tumor-promoting effects, lactate inhibits immune responses and is positively correlated with radioresistance. Dichloroacetate (DCA) is an inhibitor of pyruvate dehydrogenase kinase that decreases lactate production. Quercetin is a [...] Read more.

Elevated glucose uptake and production of lactate are common features of cancer cells. Among many tumor-promoting effects, lactate inhibits immune responses and is positively correlated with radioresistance. Dichloroacetate (DCA) is an inhibitor of pyruvate dehydrogenase kinase that decreases lactate production. Quercetin is a flavonoid compound found in fruits and vegetables that inhibits glucose uptake and lactate export. We investigated the potential role and mechanisms of DCA, quercetin, and their combination, in the treatment of HPV-positive head and neck squamous cell carcinoma, an antigenic cancer subtype in need of efficacious adjuvant therapies. C57Bl/6-derived mouse oropharyngeal epithelial cells, a previously developed mouse model that was retrovirally transduced with HPV type-16 E6/E7 and activated Ras, were used to assess these compounds. Both DCA and quercetin inhibited colony formation and reduced cell viability, which were associated with mTOR inhibition and increased apoptosis through enhanced ROS production. DCA and quercetin reduced tumor growth and enhanced survival in immune-competent mice, correlating with decreased proliferation as well as decreased acidification of the tumor microenvironment and reduction of Foxp (+) Treg lymphocytes. Collectively, these data support the possible clinical application of DCA and quercetin as adjuvant therapies for head and neck cancer patients. Full article

(This article belongs to the Special Issue Chemoprevention Advances in Cancer)

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19 pages, 6264 KiB

Open AccessArticle

Diallyl Trisulfide Induces ROS-Mediated Mitotic Arrest and Apoptosis and Inhibits HNSCC Tumor Growth and Cancer Stemness

by Sivapar V. Mathan, Ragini Singh, Su-Hyeong Kim, Shivendra V. Singh and Rana P. Singh

Cancers 2024, 16(2), 378; https://doi.org/10.3390/cancers16020378 - 16 Jan 2024

Cited by 1 | Viewed by 906

Abstract

Despite advances in therapeutic approaches, the five-year survival rate for head and neck squamous cell carcinoma (HNSCC) patients is still less than fifty percent. Research has indicated that the consumption of Allium vegetables or processed garlic containing diallyl trisulfide (DATS) can lower the [...] Read more.

Despite advances in therapeutic approaches, the five-year survival rate for head and neck squamous cell carcinoma (HNSCC) patients is still less than fifty percent. Research has indicated that the consumption of Allium vegetables or processed garlic containing diallyl trisulfide (DATS) can lower the risk of multiple types of cancer. Nevertheless, the effectiveness and underlying mechanisms of DATS against HNSCC have not been thoroughly explored until the current study. In this research, it was found that DATS notably curtailed the growth and viability of HNSCC cells. Additionally, DATS triggered a significant G2/M cell cycle arrest in these cells, accumulating cyclin B1, Cip1/p21, and Ser-10 phospho-histone H3—this was indicative of mitotic arrest attenuated by NAC pretreatment, suggesting the role of reactive oxygen species (ROS) induction. The production of ROS induced by DATS led to DNA damage and apoptosis, a process associated with elevated levels of cleaved caspase-3 and cleaved PARP, along with reduced XIAP. When HNSCC cells were exposed to pharmacological concentrations of DATS, it resulted in the suppression of cancer stem cell (CSC) populations, as indicated by a decrease in the CD133^high/CD44^high cell fraction, reduced aldehyde dehydrogenase 1 (ALDH1) activity, inhibited spheroid formation and downregulated SOX2 and Oct4 expression. Furthermore, the administration of DATS to tumor xenografts demonstrated its in vivo capacity to hinder CSCs. Further, DATS treatment inhibited the growth of UMSCC-22B head and neck cancer tumor xenograft in immunocompromised mice. Overall, DATS inhibited cell proliferation; induced cell cycle mitotic arrest and apoptosis involving DNA damage through ROS generation; reduced the CSC fraction and spheroid formation; and downregulated SOX2 and Oct4 expression. More importantly, DATS inhibited HNSCC tumor growth and CSC fraction in vivo. Thus, DATS could be a potential anticancer agent that can be used against head and neck cancer. Full article

(This article belongs to the Special Issue Chemoprevention Advances in Cancer)

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23 pages, 27875 KiB

Open AccessArticle

Differential Effect of Non-Steroidal Anti-Inflammatory Drugs Aspirin and Naproxen against TMPRSS2-ERG (Fusion)-Driven and Non-Fusion-Driven Prostate Cancer

by Komal Raina, Kushal Kandhari, Rama Kant, Ram Raj Prasad, Neha Mishra, Akhilendra K. Maurya, Jennifer T. Fox, Shizuko Sei, Robert H. Shoemaker, Maarten C. Bosland, Paul Maroni, Chapla Agarwal and Rajesh Agarwal

Cancers 2023, 15(20), 5054; https://doi.org/10.3390/cancers15205054 - 19 Oct 2023

Cited by 1 | Viewed by 1282

Abstract

The consumption of the non-steroidal anti-inflammatory drug (NSAID) aspirin is associated with a significant reduction in the risk of developing TMPRSS2-ERG (fusion)-positive prostate cancer (PCa) compared to fusion-negative PCa in population-based case–control studies; however, no extensive preclinical studies have been conducted to investigate [...] Read more.

The consumption of the non-steroidal anti-inflammatory drug (NSAID) aspirin is associated with a significant reduction in the risk of developing TMPRSS2-ERG (fusion)-positive prostate cancer (PCa) compared to fusion-negative PCa in population-based case–control studies; however, no extensive preclinical studies have been conducted to investigate and confirm these protective benefits. Thus, the focus of this study was to determine the potential usefulness of aspirin and another NSAID, naproxen, in PCa prevention, employing preclinical models of both TMPRSS2-ERG (fusion)-driven (with conditional deletion of Pten) and non-TMPRSS2-ERG-driven (Hi-Myc^+/− mice) PCa. Male mice (n = 25 mice/group) were fed aspirin- (700 and 1400 ppm) and naproxen- (200 and 400 ppm) supplemented diets from (a) 6 weeks until 32 weeks of Hi-Myc^+/− mice age; and (b) 1 week until 20 weeks post-Cre induction in the fusion model. In all NSAID-fed groups, compared to no-drug controls, there was a significant decrease in higher-grade adenocarcinoma incidence in the TMPRSS2-ERG (fusion)-driven PCa model. Notably, there were no moderately differentiated (MD) adenocarcinomas in the dorsolateral prostate of naproxen groups, and its incidence also decreased by ~79–91% in the aspirin cohorts. In contrast, NSAIDs showed little protective effect against prostate tumorigenesis in Hi-Myc^+/− mice, suggesting that NSAIDs exert a specific protective effect against TMPRSS2-ERG (fusion)-driven PCa. Full article

(This article belongs to the Special Issue Chemoprevention Advances in Cancer)

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18 pages, 5362 KiB

Open AccessArticle

Chemoprevention of Colon Cancer by DFMO, Sulindac, and NO-Sulindac Administered Individually or in Combinations in F344 Rats

by Venkateshwar Madka, Jagan M. R. Patlolla, Karthikkumar Venkatachalam, Yuting Zhang, Gopal Pathuri, Nicole Stratton, Stanley Lightfoot, Naveena B. Janakiram, Altaf Mohammed and Chinthalapally V. Rao

Cancers 2023, 15(15), 4001; https://doi.org/10.3390/cancers15154001 - 07 Aug 2023

Cited by 5 | Viewed by 1250

Abstract

Non-steroidal anti-inflammatory drugs (NSAIDs) are promising colorectal cancer (CRC) chemopreventive drugs; however, to overcome NSAIDs’ associated side effects, there is a need to develop safer and efficacious approaches. The present study was designed to evaluate (i) the efficacy of nitric-oxide releasing (NO)-Sulindac as [...] Read more.

Non-steroidal anti-inflammatory drugs (NSAIDs) are promising colorectal cancer (CRC) chemopreventive drugs; however, to overcome NSAIDs’ associated side effects, there is a need to develop safer and efficacious approaches. The present study was designed to evaluate (i) the efficacy of nitric-oxide releasing (NO)-Sulindac as compared to Sulindac; (ii) whether NO-Sulindac is superior to Sulindac in enhancing low-dose difluoromethylornithine (DFMO)-induced chemopreventive efficacy, and (iii) assessing the key biomarkers associated with colon tumor inhibition by these combinations. In F344 rats, colonic tumors were induced by azoxymethane (AOM). At the adenoma stage (13 weeks post AOM), groups of rats were fed the experimental diets containing 0 ppm, 500 ppm DFMO, 150 ppm Sulindac, and 200 ppm NO-Sulindac, individually or in combinations, for 36 weeks. Colon tumors were evaluated histopathologically and assayed for expression levels of proliferative, apoptotic, and inflammatory markers. Results suggest that (except for NO-Sulindac alone), DFMO, Sulindac individually, and DFMO combined with Sulindac or NO-Sulindac significantly suppressed AOM-induced adenocarcinoma incidence and multiplicities. DFMO and Sulindac suppressed adenocarcinoma multiplicity by 63% (p < 0.0001) and 51% (p < 0.0011), respectively, whereas NO-Sulindac had a modest effect (22.8%, p = 0.09). Combinations of DFMO plus Sulindac or NO-Sulindac suppressed adenocarcinoma incidence (60%, p < 0.0001; 50% p < 0.0004), and multiplicity (81%, p < 0.0001; 62%, p < 0.0001). Rats that were fed the combination of DFMO plus Sulindac showed significant inhibition of tumor cell proliferation and induction of apoptosis. In addition, enhancement of p21, Bax, and caspases; downregulation of Ki-67, VEGF, and β-catenin; and modulation of iNOS, COX-2, and ODC activities in colonic tumors were observed. These observations show that a lower-dose of DFMO and Sulindac significantly enhanced CRC chemopreventive efficacy when compared to NO-Sulindac alone, and the combination of DFMO and NO-Sulindac was modestly efficacious as compared to DFMO alone. Full article

(This article belongs to the Special Issue Chemoprevention Advances in Cancer)

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12 pages, 3449 KiB

Open AccessArticle

The Potent Anti-Tumor Effects of Rhodiola Drinking Are Associated with the Inhibition of the mTOR Pathway and Modification of Tumor Metabolism in the UPII-Mutant Ha-Ras Model

by Zhongbo Liu, Noriko N Yokoyama, Liankun Song, Jun Xie, Zhina Sadeghi, Yi Xi Wu, Sarah Yee, Xue-Ru Wu, Beverly Wang, Edward Uchio and Xiaolin Zi

Cancers 2023, 15(12), 3086; https://doi.org/10.3390/cancers15123086 - 07 Jun 2023

Cited by 1 | Viewed by 2979

Abstract

Background: SHR-5 has been used as an “adaptogen” for enhancing physical and mental performance and for fighting stress in the healthy population. The purpose of this study is to determine the chemopreventive efficacy of SHR-5 for superficial bladder cancer and to investigate the [...] Read more.

Background: SHR-5 has been used as an “adaptogen” for enhancing physical and mental performance and for fighting stress in the healthy population. The purpose of this study is to determine the chemopreventive efficacy of SHR-5 for superficial bladder cancer and to investigate the underlying mechanisms of action. Methods: UPII-mutant Ha-ras bladder-cancer-transgenic mice, that developed low-grade and noninvasive papillary transitional urothelial cell carcinoma, were fed with 1.25 and 6.25 mg/mL SHR-5 in drinking water for 6 months. The survival of the mice, obstructive uropathy, tumor burden and morphology, and proliferation were evaluated by pathological, molecular, metabolic, and statistical analyses. Results: Approximately 95% or more of the male UPII-mutant Ha-ras mice that drank SHR-5 daily survived over 6 months of age, while only 33.3% of those mice that drank normal water survived over 6 months of age (p < 0.0001); SHR-5 drinking exposure also reduced tumor-bearing bladder weight and urinary tract obstruction and inhibited mTOR signaling in neoplastic tissues. Global metabolic analysis revealed that SHR-5 resulted in increased phenolic metabolites and decreased CoA, a critical metabolic cofactor for lipid metabolism. Conclusions: Our findings highlight the potential of SHR-5 as an anti-aging agent for bladder cancer prevention through reshaping tumor metabolism via the inhibition of the mTOR signaling. Global metabolomics profiling provides a unique and efficient tool for studying the mechanisms of complex herb extracts’ action. Full article

(This article belongs to the Special Issue Chemoprevention Advances in Cancer)

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10 pages, 295 KiB

Open AccessArticle

Association between the Processed Dietary Pattern and Tumor Staging in Patients Newly Diagnosed with Head and Neck Squamous Cell Carcinoma

by Ana Carolina da Silva Lima, Tathiany Jéssica Ferreira, Adriana Divina de Souza Campos, Larissa Morinaga Matida, Maria Beatriz Trindade Castro, Ana Amélia Freitas-Vilela and Maria Aderuza Horst

Cancers 2023, 15(5), 1476; https://doi.org/10.3390/cancers15051476 - 25 Feb 2023

Viewed by 1285

Abstract

Purpose: This study aimed to assess the association between dietary patterns and tumor staging and the degree of cell differentiation in patients with head and neck squamous cell carcinoma (HNSCC). Methods: This cross-sectional study included 136 individuals newly diagnosed with different stages of [...] Read more.

Purpose: This study aimed to assess the association between dietary patterns and tumor staging and the degree of cell differentiation in patients with head and neck squamous cell carcinoma (HNSCC). Methods: This cross-sectional study included 136 individuals newly diagnosed with different stages of HNSCC, aged 20- to 80 years-old. Dietary patterns were determined by principal component analysis (PCA), using data collected from a food frequency questionnaire (FFQ). Anthropometric, lifestyle, and clinicopathological data were collected from patients’ medical records. Disease staging was categorized as initial stage (stages I and II), intermediary (stage III), and advanced (stage IV). Cell differentiation was categorized as poor, moderate, or well-differentiated. The association of dietary patterns with tumor staging and cell differentiation was evaluated using multinomial logistic regression models and adjusted for potential confounders. Results: Three dietary patterns, “healthy,” “processed,” and “mixed,” were identified. The “processed” dietary pattern was associated with intermediary (odds ratio (OR) 2.47; 95% confidence interval (CI) 1.43–4.26; p = 0.001) and advanced (OR 1.78; 95% CI 1.12–2.84; p = 0.015) staging. No association was found between dietary patterns and cell differentiation. Conclusion: A high adherence to dietary patterns based on processed foods is associated with advanced tumor staging in patients newly diagnosed with HNSCC. Full article

(This article belongs to the Special Issue Chemoprevention Advances in Cancer)

14 pages, 4307 KiB

Open AccessArticle

Timosaponin AIII Inhibits Migration and Invasion Abilities in Human Cervical Cancer Cells through Inactivation of p38 MAPK-Mediated uPA Expression In Vitro and In Vivo

by Hung-Ju Chien, Chung-Jung Liu, Tsung-Ho Ying, Pei-Ju Wu, Jiunn-Wei Wang, Yi-Hsuan Ting, Yi-Hsien Hsieh and Shih-Chiang Wang

Cancers 2023, 15(1), 37; https://doi.org/10.3390/cancers15010037 - 21 Dec 2022

Cited by 6 | Viewed by 1740

Abstract

Cervical cancer is one of the most common gynecologic cancers globally that require novel approaches. Timosaponin AIII (TSAIII) is a steroidal saponin that displays beneficial effects in antitumor activities. However, the effect of TSAIII on human cervical cancer remains unknown. In this study, [...] Read more.

Cervical cancer is one of the most common gynecologic cancers globally that require novel approaches. Timosaponin AIII (TSAIII) is a steroidal saponin that displays beneficial effects in antitumor activities. However, the effect of TSAIII on human cervical cancer remains unknown. In this study, we found that TSAIII showed no influence on cell viability, cytotoxicity, cell cycle distribution and apoptosis induction in human cervical cancer cells. TSAIII was revealed to have a significant inhibitory effect on cell migration and invasion through the downregulation of invasion-related uPA expression and p38 MAPK activation in both human cervical cancer cells and cervical cancer stem cells (CCSCs), indicating that the p38 MAPK–uPA axis mediated the TSAIII-inhibited capacity of cellular migration and invasion. In a synergistic inhibition assay, a TSAIII plus p38 siRNA cotreatment revealed a greater inhibition of uPA expression, migration and invasion in human cervical cancer cells. In an immunodeficient mouse model, TSAIII significantly inhibited lung metastases from human cervical cancer SiHa cells without TSAIII-induced toxicity. These findings first revealed the inhibitory effects of TSAIII on the progression of human cervical cancer through its downregulation of p38 MAPK–uPA axis activation. Therefore, TSAIII might provide a potential strategy for auxiliary therapy in human cervical cancer. Full article

(This article belongs to the Special Issue Chemoprevention Advances in Cancer)

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Review

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18 pages, 3248 KiB

Open AccessReview

The Promise of Piperine in Cancer Chemoprevention

by Salma Benayad, Hicham Wahnou, Riad El Kebbaj, Bertrand Liagre, Vincent Sol, Mounia Oudghiri, El Madani Saad, Raphaël Emmanuel Duval and Youness Limami

Cancers 2023, 15(22), 5488; https://doi.org/10.3390/cancers15225488 - 20 Nov 2023

Cited by 3 | Viewed by 1424

Abstract

Cancer, characterized by the unregulated growth and dissemination of malignantly transformed cells, presents a significant global health challenge. The multistage process of cancer development involves intricate biochemical and genetic alterations within target cells. Cancer chemoprevention has emerged as a vital strategy to address [...] Read more.

Cancer, characterized by the unregulated growth and dissemination of malignantly transformed cells, presents a significant global health challenge. The multistage process of cancer development involves intricate biochemical and genetic alterations within target cells. Cancer chemoprevention has emerged as a vital strategy to address this complex issue to mitigate cancer’s impact on healthcare systems. This approach leverages pharmacologically active agents to block, suppress, prevent, or reverse invasive cancer development. Among these agents, piperine, an active alkaloid with a wide range of therapeutic properties, including antioxidant, anti-inflammatory, and immunomodulatory effects, has garnered attention for its potential in cancer prevention and treatment. This comprehensive review explores piperine’s multifaceted role in inhibiting the molecular events and signaling pathways associated with various stages of cancer development, shedding light on its promising prospects as a versatile tool in cancer chemoprevention. Furthermore, the review will also delve into how piperine enhances the effectiveness of conventional treatments such as UV-phototherapy and TRAIL-based therapy, potentially synergizing with existing therapeutic modalities to provide more robust cancer management strategies. Finally, a crucial perspective of the long-term safety and potential side effects of piperine-based therapies and the need for clinical trials is also discussed. Full article

(This article belongs to the Special Issue Chemoprevention Advances in Cancer)

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