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Pharmaceuticals
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Naturally-Occurring Dietary Compounds for Cancer Prevention and Therapy
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Naturally-Occurring Dietary Compounds for Cancer Prevention and Therapy

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Natural Products".

Deadline for manuscript submissions: closed (31 October 2023) | Viewed by 12338

Special Issue Editors

Dr. John F. Lechner

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Guest Editor
Retired from The Ohio State University Comprehensive Cancer Center, 2001 Polaris Parkway, Columbus, OH 43210, USA
Interests: cancer chemoprevention; chemical carcinogenesis
Prof. Dr. Gary D. Stoner

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Guest Editor
Department of Medicine, College of Medicine, The Ohio State University, Columbus, OH 43210, USA
Interests: chemoprevention; nutraceuticals; chemical carcinogenesis; esophagus; lung cancer
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Compounds that prevent the initiation of premalignant lesions and their progression to malignancy are referred to as being cancer chemopreventive. To date, more than 1,000 substances have been evaluated and many were shown to prevent cancer. Several of these originated from dietary sources. Mechanistically, chemopreventive agents have been shown to exhibit both anti-tumor initiation and -tumor promotion effects. They inhibit tumor initiation by reducing the activity of enzymes involved in the metabolic activation of carcinogens into metabolites that produce DNA damage and/or by enhancing the activity of enzymes involved in carcinogen detoxification. In addition, they reduce oxidative damage to DNA and other cellular macromolecules by their ability to scavenge oxidative radicals. They inhibit tumor promotion/progression by multiple mechanisms such as reducing abnormal cell proliferation, inflammation, angiogenesis, tissue invasion and metastasis and promoting cell differentiation and programmed cell death (apoptosis). One interesting but poorly understood feature of chemopreventive agents is their ability to selectively inhibit the abnormal cells undergoing carcinogenesis, while not perturbing the normal cells. The most promising chemopreventive agents appear to be those which affect multiple cellular functions at doses that elicit little or no toxicity. Unfortunately, however, most chemopreventive agents that exhibit inhibitory activity in animal model tumor systems have been either ineffective or exhibited tumor promotional effects in humans.

In contrast, chemotherapeutic drugs are selected for use in cancer treatment largely by their ability to kill cancer cells either by direct damage to DNA and other cellular macromolecules or by targeting specific genes and their proteins in cellular signaling pathways. Chemotherapy is often used in conjunction with radiotherapy and/or with surgery in cases where surgery does not result in complete removal of the tumor. Recently, multiple studies are ongoing to evaluate the ability of chemotherapeutic drugs to enhance the effectiveness of immunotherapy for cancer treatment. Some tumor types appear to be treated quite effectively by immunotherapy.

Relatively few preclinical and clinical studies have evaluated the effects of using chemopreventive agents and chemotherapeutic drugs in combination for cancer treatment. In view of the wide range of cellular and molecular effects of chemopreventive agents, it seems logical that they could contribute significantly to the efficacy of chemotherapeutic drugs in cancer therapy. For example, chemopreventive agents might be expected to reduce the toxic effects of chemotherapeutic drugs on normal tissues. Similarly, the mechanisms described above by which they influence events in tumor promotion/progression would seem likely to add appreciably to the effectiveness of chemotherapy.  Thus, the purpose of this special issue in Pharmaceuticals is to identify some of the most promising chemopreventive agents and describe their mechanisms of action and to present some investigations that suggest the efficacy of using chemoprevention in combination with chemotherapy for cancer treatment.

Dr. John F. Lechner
Prof. Dr. Gary D. Stoner
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceuticals is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • naturally- occurring chemopreventive agents
  • cellular effects
  • molecular effects
  • chemoprevention + chemotherapy for cancer treatment

Published Papers (8 papers)

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Research

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25 pages, 1760 KiB  
Article
Cranberry Proanthocyanidins Mitigate Reflux-Induced Transporter Dysregulation in an Esophageal Adenocarcinoma Model
by Yun Zhang, Katherine M. Weh, Bridget A. Tripp, Jennifer L. Clarke, Connor L. Howard, Shruthi Sunilkumar, Amy B. Howell and Laura A. Kresty
Pharmaceuticals 2023, 16(12), 1697; https://doi.org/10.3390/ph16121697 - 7 Dec 2023
Viewed by 1322
Abstract
We recently reported that cranberry proanthocyanidins (C-PACs) inhibit esophageal adenocarcinoma (EAC) by 83% through reversing reflux-induced bacterial, inflammatory and immune-implicated proteins and genes as well as reducing esophageal bile acids, which drive EAC progression. This study investigated whether C-PACs’ mitigation of bile reflux-induced [...] Read more.
We recently reported that cranberry proanthocyanidins (C-PACs) inhibit esophageal adenocarcinoma (EAC) by 83% through reversing reflux-induced bacterial, inflammatory and immune-implicated proteins and genes as well as reducing esophageal bile acids, which drive EAC progression. This study investigated whether C-PACs’ mitigation of bile reflux-induced transporter dysregulation mechanistically contributes to EAC prevention. RNA was isolated from water-, C-PAC- and reflux-exposed rat esophagi with and without C-PAC treatment. Differential gene expression was determined by means of RNA sequencing and RT-PCR, followed by protein assessments. The literature, coupled with the publicly available Gene Expression Omnibus dataset GSE26886, was used to assess transporter expression levels in normal and EAC patient biopsies for translational relevance. Significant changes in ATP-binding cassette (ABC) transporters implicated in therapeutic resistance in humans (i.e., Abcb1, Abcb4, Abcc1, Abcc3, Abcc4, Abcc6 and Abcc10) and the transport of drugs, xenobiotics, lipids, and bile were altered in the reflux model with C-PACs’ mitigating changes. Additionally, C-PACs restored reflux-induced changes in solute carrier (SLC), aquaporin, proton and cation transporters (i.e., Slc2a1, Slc7a11, Slc9a1, Slco2a1 and Atp6v0c). This research supports the suggestion that transporters merit investigation not only for their roles in metabolism and therapeutic resistance, but as targets for cancer prevention and targeting preventive agents in combination with chemotherapeutics. Full article
(This article belongs to the Special Issue Naturally-Occurring Dietary Compounds for Cancer Prevention and Therapy)
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15 pages, 5844 KiB  
Article
The Chemoprevention Effects of Two Herbal Mixtures on Chemically Induced Lung Tumorigenesis in Mice
by Chunjie Li, Yian Wang, Song Gao, Ming Hu and Ming You
Pharmaceuticals 2023, 16(12), 1666; https://doi.org/10.3390/ph16121666 - 30 Nov 2023
Viewed by 777
Abstract
Ruan Hua Tang (RHT) and Ruan Hua Fang (RHF) are two Chinese herbal mixtures that have been used in clinical cancer treatment for decades. This study validated our hypothesis that RHT and RHF can inhibit lung tumor development in the mouse model of [...] Read more.
Ruan Hua Tang (RHT) and Ruan Hua Fang (RHF) are two Chinese herbal mixtures that have been used in clinical cancer treatment for decades. This study validated our hypothesis that RHT and RHF can inhibit lung tumor development in the mouse model of Benzo(a)pyrene-induced lung tumorigenesis. An RHT oral solution was diluted to 9% and 18% in water. RHF was mixed into the diet at 15% and 30% of total food in the final doses. Two weeks after injecting BP into mice, we administered RHT and RHF for eighteen weeks. We found that 9% and 18% RHT reduced tumor multiplicity by 36.05% and 38.81% (both p < 0.05) and the tumor load by 27.13% and 55.94% (p < 0.05); 15% and 30% RHF inhibited tumor multiplicity by 12.75% and 39.84% (p < 0.01) and the tumor load by 18.38% and 61.68% (p < 0.05). Ki67 expressions in the 9% and 18% RHT groups were 19.55% and 11.51%, significantly lower than in the control (33.64%). The Ki67 levels in the 15% and 30% RHF groups were 15.56% and 14.04%, significantly lower than in the control (27.86%). Caspase 3 expressions in the 9% and 18% RHT groups were 5.24% and 7.32%, significantly higher than in the control (2.39%). Caspase 3 levels in the 15% and 30% RHF groups were 6.53% and 4.74%, significantly higher than in the control (2.07%). The bio-absorption was confirmed via a pharmacokinetic test. This study showed that RHT and RHF are safe and can inhibit lung tumor development, with anti-proliferative and pro-apoptotic effects. Full article
(This article belongs to the Special Issue Naturally-Occurring Dietary Compounds for Cancer Prevention and Therapy)
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12 pages, 3465 KiB  
Article
Complementarity between Microbiome and Immunity May Account for the Potentiating Effect of Quercetin on the Antitumor Action of Cyclophosphamide in a Triple-Negative Breast Cancer Model
by Andrea Manni, Yuan-Wan Sun, Todd D. Schell, Tymofiy Lutsiv, Henry Thompson, Kun-Ming Chen, Cesar Aliaga, Junjia Zhu and Karam El-Bayoumy
Pharmaceuticals 2023, 16(10), 1422; https://doi.org/10.3390/ph16101422 - 6 Oct 2023
Viewed by 1181
Abstract
Immunotherapy targeting program cell death protein 1 (PD-1) in addition to chemotherapy has improved the survival of triple-negative breast cancer (TNBC) patients. However, the development of resistance and toxicity remain significant problems. Using the translationally relevant 4T1 mouse model of TNBC, we report [...] Read more.
Immunotherapy targeting program cell death protein 1 (PD-1) in addition to chemotherapy has improved the survival of triple-negative breast cancer (TNBC) patients. However, the development of resistance and toxicity remain significant problems. Using the translationally relevant 4T1 mouse model of TNBC, we report here that dietary administration of the phytochemical quercetin enhanced the antitumor action of Cyclophosphamide, a cytotoxic drug with significant immunogenic effects that is part of the combination chemotherapy used in TNBC. We observed that quercetin favorably modified the host fecal microbiome by enriching species such as Akkermansia muciniphilia, which has been shown to improve response to anti-PD-1 therapy. We also show that quercetin and, to a greater extent, Cyclophosphamide increased the systemic frequency of T cells and NK cells. In addition, Cyclophosphamide alone and in combination with quercetin reduced the frequency of Treg, which is consistent with an antitumor immune response. On the other hand, Cyclophosphamide did not significantly alter the host microbiome, suggesting complementarity between microbiome- and immune-mediated mechanisms in potentiating the antitumor action of Cyclophosphamide by quercetin. Overall, these results support the potential for microbiota-centered dietary intervention to overcome resistance to chemoimmunotherapy in TNBC. Full article
(This article belongs to the Special Issue Naturally-Occurring Dietary Compounds for Cancer Prevention and Therapy)
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Review

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17 pages, 444 KiB  
Review
Natural Products for Cancer Prevention and Interception: Preclinical and Clinical Studies and Funding Opportunities
by Edward R. Sauter and Altaf Mohammed
Pharmaceuticals 2024, 17(1), 136; https://doi.org/10.3390/ph17010136 - 20 Jan 2024
Cited by 1 | Viewed by 2270
Abstract
Multiple agents derived from natural products (NPs) have been evaluated for cancer prevention and interception, either alone or in combination. The National Cancer Institute (NCI) is very interested in advancing research to identify additional agents that, alone or in combination, may prove useful [...] Read more.
Multiple agents derived from natural products (NPs) have been evaluated for cancer prevention and interception, either alone or in combination. The National Cancer Institute (NCI) is very interested in advancing research to identify additional agents that, alone or in combination, may prove useful in cancer prevention. Below, we provide an overview of NP studies in cancer prevention and interception, both individual agents and combination interventions. Given that findings from many preclinical studies evaluating individual agents have generally not been confirmed in human studies, our focus with individual NPs in this review is on studies involving humans, especially clinical trials. Fewer combination intervention studies have been conducted, so we have broadened our review to include preclinical studies. We conclude with how the Division of Cancer Prevention (DCP) within the NCI is providing funding to encourage the research community to propose natural product studies in cancer prevention and interception to advance the field. Full article
(This article belongs to the Special Issue Naturally-Occurring Dietary Compounds for Cancer Prevention and Therapy)
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24 pages, 1475 KiB  
Review
Berries vs. Disease: Revenge of the Phytochemicals
by Felipe F. Lamenza, Puja Upadhaya, Peyton Roth, Suvekshya Shrestha, Sushmitha Jagadeesha, Natalie Horn, Hasan Pracha and Steve Oghumu
Pharmaceuticals 2024, 17(1), 84; https://doi.org/10.3390/ph17010084 - 9 Jan 2024
Viewed by 1639
Abstract
Secondary metabolites and phytochemicals in plant-based diets are known to possess properties that inhibit the development of several diseases including a variety of cancers of the aerodigestive tract. Berries are currently of high interest to researchers due to their high dietary source of [...] Read more.
Secondary metabolites and phytochemicals in plant-based diets are known to possess properties that inhibit the development of several diseases including a variety of cancers of the aerodigestive tract. Berries are currently of high interest to researchers due to their high dietary source of phytochemicals. Black raspberries (BRB), Rubus occidentalis, are of special interest due to their rich and diverse composition of phytochemicals. In this review, we present the most up-to-date preclinical and clinical data involving berries and their phytochemicals in the chemoprevention of a variety of cancers and diseases. BRBs possess a variety of health benefits including anti-proliferative properties, anti-inflammatory activity, activation of pro-cell-death pathways, modulation of the immune response, microbiome modulation, reduction in oxidative stress, and many more. However, little has been done in both preclinical and clinical settings on the effects of BRB administration in combination with other cancer therapies currently available for patients. With the high potential for BRBs as chemopreventive agents, there is a need to investigate their potential in combination with other treatments to improve therapeutic efficacy. Full article
(This article belongs to the Special Issue Naturally-Occurring Dietary Compounds for Cancer Prevention and Therapy)
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17 pages, 1969 KiB  
Review
Research Progress on the Synergistic Anti-Tumor Effect of Natural Anti-Tumor Components of Chinese Herbal Medicine Combined with Chemotherapy Drugs
by Hongrui Zhou, Mengxue Zhang, Huihui Cao, Xintong Du, Xin Zhang, Jin Wang and Xiuli Bi
Pharmaceuticals 2023, 16(12), 1734; https://doi.org/10.3390/ph16121734 - 15 Dec 2023
Cited by 1 | Viewed by 1098
Abstract
The application of chemotherapy drugs in tumor treatment has a long history, but the lack of selectivity of drugs often leads to serious side effects during chemotherapy. The natural anti-tumor ingredients derived from Chinese herbal medicine are attracting increased attention due to their [...] Read more.
The application of chemotherapy drugs in tumor treatment has a long history, but the lack of selectivity of drugs often leads to serious side effects during chemotherapy. The natural anti-tumor ingredients derived from Chinese herbal medicine are attracting increased attention due to their diverse anti-tumor effects, abundant resources, and minimal side effects. An effective anti-tumor strategy may lie in the combination of these naturally derived anti-tumor ingredients with conventional chemotherapy drugs. This approach could potentially inhibit tumor growth and the development of drug resistance in tumor cells while reducing the adverse effects of chemotherapy drugs. This review provides a comprehensive overview of the combined therapy strategies integrating natural anti-tumor components from Chinese herbal medicine with chemotherapy drugs in current research. We primarily summarize various compounds in Chinese herbal medicine exhibiting natural anti-tumor activities and the relevant mechanisms in synergistic anti-tumor combination therapy. The focus of this paper is on underlining that this integrative approach, combining natural anti-tumor components of Chinese herbal medicine with chemotherapy drugs, presents a novel cancer treatment methodology, thereby providing new insights for future oncological research. Full article
(This article belongs to the Special Issue Naturally-Occurring Dietary Compounds for Cancer Prevention and Therapy)
25 pages, 5606 KiB  
Review
Phytochemicals as Immunomodulatory Molecules in Cancer Therapeutics
by Sandeep Paudel, Neha Mishra and Rajesh Agarwal
Pharmaceuticals 2023, 16(12), 1652; https://doi.org/10.3390/ph16121652 - 26 Nov 2023
Cited by 2 | Viewed by 2226
Abstract
Phytochemicals are natural plant-derived products that provide significant nutrition, essential biomolecules, and flavor as part of our diet. They have long been known to confer protection against several diseases via their anti-inflammatory, immune-regulatory, anti-microbial, and several other properties. Deciphering the role of phytochemicals [...] Read more.
Phytochemicals are natural plant-derived products that provide significant nutrition, essential biomolecules, and flavor as part of our diet. They have long been known to confer protection against several diseases via their anti-inflammatory, immune-regulatory, anti-microbial, and several other properties. Deciphering the role of phytochemicals in the prevention, inhibition, and treatment of cancer—unrestrained cell proliferation due to the loss of tight regulation on cell growth and replication—has been the focus of recent research. Particularly, the immunomodulatory role of phytochemicals, which is pivotal in unchecked cell proliferation and metastasis, has recently been studied extensively. The immune system is a critical component of the tumor microenvironment, and it plays essential roles in both preventing and promoting oncogenesis. Immunomodulation includes stimulation, amplification, or inactivation of some stage(s) of the immune response. Phytochemicals and their products have demonstrated immune regulation, such as macrophage migration, nitric oxide synthase inhibition, lymphocyte, T-cell, and cytokine stimulation, natural killer cell augmentation, and NFκB, TNF, and apoptosis regulation. There is a dearth of extensive accounts of the immunomodulatory effects of phytochemicals in cancer; thus, we have compiled these effects with mechanistic aspects of dietary phytochemicals in cancer, highlighting promising candidates and ongoing clinical trials on immunotherapeutic strategies to mitigate oncogenesis. Full article
(This article belongs to the Special Issue Naturally-Occurring Dietary Compounds for Cancer Prevention and Therapy)
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15 pages, 649 KiB  
Review
Potential Chemopreventive Effects of Dietary Combination of Phytochemicals against Cancer Development
by Takuji Tanaka, Ryogo Aoki and Masaru Terasaki
Pharmaceuticals 2023, 16(11), 1591; https://doi.org/10.3390/ph16111591 - 10 Nov 2023
Cited by 3 | Viewed by 1234
Abstract
Cancer remains a major cause of cancer-related death worldwide. Over 70% of epithelial malignancies are sporadic and are related to lifestyle. Epidemiological studies suggest an inverse correlation between cancer incidence and fruit and vegetable intake. Numerous preclinical studies using in vitro (cell lines) [...] Read more.
Cancer remains a major cause of cancer-related death worldwide. Over 70% of epithelial malignancies are sporadic and are related to lifestyle. Epidemiological studies suggest an inverse correlation between cancer incidence and fruit and vegetable intake. Numerous preclinical studies using in vitro (cell lines) and in vivo animal models of oncogenesis have reported the chemopreventive effects of dietary phytochemical agents through alterations in different biomarkers and signaling pathways. However, there is contrasting evidence from preclinical studies and clinical trials. To date, the most studied compounds include curcumin, resveratrol, isoflavones, green tea extract (epigallocatechin gallate), black raspberry powder (anthocyanins and ellagitannins), bilberry extract (anthocyanins), ginger extract (gingerol derivatives), and pomegranate extract (ellagitannins and ellagic acid). Overall, the clinical evidence of the preventive effects of dietary phytochemicals against cancer development is still weak, and the amount of these phytochemicals needed to exert chemopreventive effects largely exceeds the common dietary doses. Therefore, we propose a combination treatment of natural compounds that are used clinically for another purpose in order to obtain excess inhibitory efficacy via low-dose administration and discuss the possible reasons behind the gap between preclinical research and clinical trials. Full article
(This article belongs to the Special Issue Naturally-Occurring Dietary Compounds for Cancer Prevention and Therapy)
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