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Evolution of Cancer Pharmacological Treatment: Natural Compounds as Adjuvants for Cancer Treatments

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: closed (15 May 2023) | Viewed by 12931

Special Issue Editors

Dr. Laura Mosca

E-Mail Website
Guest Editor
Department of Precision Medicine, University of Campania Luigi Vanvitelli, 80138 Naples, Italy
Interests: glioblastoma; cancers; natural compounds; miRNAs; colorectal cancer
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Bonglee Kim

E-Mail Website
Guest Editor
Department of Pathology, College of Korean Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
Interests: oncology; epigenetics; miRNA; natural products; cancer; antioxidants; apoptosis
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Cancer is one of the leading causes of death worldwide despite significant progress in both early diagnosis and therapy. Different anticancer treatments based on chemotherapy drugs fail due to adverse reactions, drug resistance, and loss of target specificity. Therefore, there is a strong interest to find new molecules with antitumor activity and less therapeutic toxicity than the currently used drugs and which are, at the same time, effective against several cancer types. In this light, there is a strong interest in identifying and developing new cancer treatments, taking advantage on the combination of natural compounds and cytotoxic agents, in order to improve therapeutic efficacy by reducing side effects and overcoming drug resistance mechanisms.

Dr. Laura Mosca
Dr. Bonglee Kim
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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

  • cancer
  • natural compounds
  • herbal medicines
  • microRNAs
  • drug resistance
  • combination therapy

Published Papers (7 papers)

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Research

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18 pages, 4032 KiB  
Article
Suppression of TGFβ-Induced Interleukin-6 Secretion by Sinulariolide from Soft Corals through Attenuation of the p38–NF-kB Pathway in Carcinoma Cells
by Jenq-Lin Yang, Weng-Ling Lin, Shun-Ban Tai, Yi-Siang Ciou, Chih-Ling Chung, Jih-Jung Chen, Pei-Feng Liu, Ming-Wei Lin and Chun-Lin Chen
Int. J. Mol. Sci. 2023, 24(14), 11656; https://doi.org/10.3390/ijms241411656 - 19 Jul 2023
Viewed by 1284
Abstract
Sinulariolide (SC-1) is a natural product extracted from the cultured-type soft coral Sinularia flexibilis and possesses anti-inflammation, anti-proliferative, and anti-migratory in several types of cancer cells. However, the molecular pathway behind its effects on inflammation remains poorly understood. Since inflammatory cytokines such as [...] Read more.
Sinulariolide (SC-1) is a natural product extracted from the cultured-type soft coral Sinularia flexibilis and possesses anti-inflammation, anti-proliferative, and anti-migratory in several types of cancer cells. However, the molecular pathway behind its effects on inflammation remains poorly understood. Since inflammatory cytokines such as TGFβ, TNFα, IL-1, IL-6, and IL-8 activate transcription factors such as Smads, NF-κB, STAT3, Snail, Twist, and Zeb that drive the epithelial-to-mesenchymal transition (EMT), in this study, we focus on the investigation in effects of SC-1 on TGFβ-induced interleukin-6 (IL-6) releases in an in vitro cell culture model. We showed that both intracellular IL-6 expression and secretion were stimulated by TGFβ and associated with strong upregulation of IL-6 mRNA and increased transcription in A549 cells. SC-1 blocked TGFβ-induced secretion of IL-6 while showing no effect on the induction of fibronectin and plasminogen activator inhibitor-1 genes, indicating that SC-1 interferes with only a subset of TGFβ activities. In addition, SC-1 inhibits TGFβ-induced IL-6 by suppressing p38 MAPK signaling and subsequently inhibits NF-κB and its nuclear translocation without affecting the canonical Smad pathway and receptor turnover. Overall, these data suggest that p38 may involve in the inhibition of SC-1 in IL-6 release, thus illustrating an inhibitory effect for SC-1 in the suppression of inflammation, EMT phenotype, and tumorigenesis. Full article
(This article belongs to the Special Issue Evolution of Cancer Pharmacological Treatment: Natural Compounds as Adjuvants for Cancer Treatments)
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23 pages, 4657 KiB  
Article
α-Tocopherol-13′-Carboxychromanol Induces Cell Cycle Arrest and Cell Death by Inhibiting the SREBP1-SCD1 Axis and Causing Imbalance in Lipid Desaturation
by Sijia Liao, André Gollowitzer, Lisa Börmel, Charlotte Maier, Luisa Gottschalk, Oliver Werz, Maria Wallert, Andreas Koeberle and Stefan Lorkowski
Int. J. Mol. Sci. 2023, 24(11), 9229; https://doi.org/10.3390/ijms24119229 - 25 May 2023
Cited by 1 | Viewed by 1313
Abstract
α-Tocopherol-13′-carboxychromanol (α-T-13′-COOH) is an endogenously formed bioactive α-tocopherol metabolite that limits inflammation and has been proposed to exert lipid metabolism-regulatory, pro-apoptotic, and anti-tumoral properties at micromolar concentrations. The mechanisms underlying these cell stress-associated responses are, however, poorly understood. Here, we show that the [...] Read more.
α-Tocopherol-13′-carboxychromanol (α-T-13′-COOH) is an endogenously formed bioactive α-tocopherol metabolite that limits inflammation and has been proposed to exert lipid metabolism-regulatory, pro-apoptotic, and anti-tumoral properties at micromolar concentrations. The mechanisms underlying these cell stress-associated responses are, however, poorly understood. Here, we show that the induction of G0/G1 cell cycle arrest and apoptosis in macrophages triggered by α-T-13′-COOH is associated with the suppressed proteolytic activation of the lipid anabolic transcription factor sterol regulatory element-binding protein (SREBP)1 and with decreased cellular levels of stearoyl-CoA desaturase (SCD)1. In turn, the fatty acid composition of neutral lipids and phospholipids shifts from monounsaturated to saturated fatty acids, and the concentration of the stress-preventive, pro-survival lipokine 1,2-dioleoyl-sn-glycero-3-phospho-(1′-myo-inositol) [PI(18:1/18:1)] decreases. The selective inhibition of SCD1 mimics the pro-apoptotic and anti-proliferative activity of α-T-13′-COOH, and the provision of the SCD1 product oleic acid (C18:1) prevents α-T-13′-COOH-induced apoptosis. We conclude that micromolar concentrations of α-T-13′-COOH trigger cell death and likely also cell cycle arrest by suppressing the SREBP1-SCD1 axis and depleting cells of monounsaturated fatty acids and PI(18:1/18:1). Full article
(This article belongs to the Special Issue Evolution of Cancer Pharmacological Treatment: Natural Compounds as Adjuvants for Cancer Treatments)
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29 pages, 5089 KiB  
Article
Sequential Treatment with Temozolomide Plus Naturally Derived AT101 as an Alternative Therapeutic Strategy: Insights into Chemoresistance Mechanisms of Surviving Glioblastoma Cells
by Dana Hellmold, Carolin Kubelt, Tina Daunke, Silje Beckinger, Ottmar Janssen, Margarethe Hauck, Fabian Schütt, Rainer Adelung, Ralph Lucius, Jochen Haag, Susanne Sebens, Michael Synowitz and Janka Held-Feindt
Int. J. Mol. Sci. 2023, 24(10), 9075; https://doi.org/10.3390/ijms24109075 - 22 May 2023
Viewed by 1431
Abstract
Glioblastoma (GBM) is a poorly treatable disease due to the fast development of tumor recurrences and high resistance to chemo- and radiotherapy. To overcome the highly adaptive behavior of GBMs, especially multimodal therapeutic approaches also including natural adjuvants have been investigated. However, despite [...] Read more.
Glioblastoma (GBM) is a poorly treatable disease due to the fast development of tumor recurrences and high resistance to chemo- and radiotherapy. To overcome the highly adaptive behavior of GBMs, especially multimodal therapeutic approaches also including natural adjuvants have been investigated. However, despite increased efficiency, some GBM cells are still able to survive these advanced treatment regimens. Given this, the present study evaluates representative chemoresistance mechanisms of surviving human GBM primary cells in a complex in vitro co-culture model upon sequential application of temozolomide (TMZ) combined with AT101, the R(-) enantiomer of the naturally occurring cottonseed-derived gossypol. Treatment with TMZ+AT101/AT101, although highly efficient, yielded a predominance of phosphatidylserine-positive GBM cells over time. Analysis of the intracellular effects revealed phosphorylation of AKT, mTOR, and GSK3ß, resulting in the induction of various pro-tumorigenic genes in surviving GBM cells. A Torin2-mediated mTOR inhibition combined with TMZ+AT101/AT101 partly counteracted the observed TMZ+AT101/AT101-associated effects. Interestingly, treatment with TMZ+AT101/AT101 concomitantly changed the amount and composition of extracellular vesicles released from surviving GBM cells. Taken together, our analyses revealed that even when chemotherapeutic agents with different effector mechanisms are combined, a variety of chemoresistance mechanisms of surviving GBM cells must be taken into account. Full article
(This article belongs to the Special Issue Evolution of Cancer Pharmacological Treatment: Natural Compounds as Adjuvants for Cancer Treatments)
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15 pages, 2779 KiB  
Article
Antiproliferative Effects of Cynara Cardunculus in Colorectal Cancer Cells Are Modulated by the Circadian Clock
by Luise Fuhr, Alireza Basti, Teresa Silva Brás, Maria F. Duarte and Angela Relógio
Int. J. Mol. Sci. 2022, 23(16), 9130; https://doi.org/10.3390/ijms23169130 - 15 Aug 2022
Cited by 2 | Viewed by 1645
Abstract
The circadian clock generates 24 h rhythms in behavioural, cellular and molecular processes. Malfunctions of the clock are associated with enhanced susceptibility to cancer, worse treatment response and poor prognosis. Clock-controlled genes are involved in cellular processes associated with tumour development and progression [...] Read more.
The circadian clock generates 24 h rhythms in behavioural, cellular and molecular processes. Malfunctions of the clock are associated with enhanced susceptibility to cancer, worse treatment response and poor prognosis. Clock-controlled genes are involved in cellular processes associated with tumour development and progression including metabolism of drugs and the cell cycle. Cynara cardunculus, a plant of the Asteraceae family, has been reported to have antiproliferative effects on breast cancer cells. Here, we used the human colorectal cancer (CRC) cell line HCT116 and its knockout variants for different core-clock genes (BMAL1, PER2, NR1D1), to investigate the treatment effect of C. cardunculus lipophilic leaf extract under different clock scenarios. Our results show a direct effect of C. cardunculus on the circadian phenotype of the cells, as indicated by alterations in the phase, amplitude, and period length of core-clock gene oscillations. Furthermore, our data indicate a role for the circadian clock in sensitivity to C. cardunculus treatment. In particular, the treatment inhibited proliferation and induced cytotoxicity and apoptosis in a clock knockout-specific manner, in CRC cells. These results point to a potential effect of C. cardunculus lipophilic leaf extracts as a modulator of the circadian clock, in addition to its anti-proliferative properties. Full article
(This article belongs to the Special Issue Evolution of Cancer Pharmacological Treatment: Natural Compounds as Adjuvants for Cancer Treatments)
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10 pages, 9236 KiB  
Article
Light-Induced Activation of a Specific Type-5 Metabotropic Glutamate Receptor Antagonist in the Ventrobasal Thalamus Causes Analgesia in a Mouse Model of Breakthrough Cancer Pain
by Serena Notartomaso, Nico Antenucci, Francesca Liberatore, Giada Mascio, Stefano Vito Boccadamo Pompili, Joan Font, Mariarosaria Scioli, Livio Luongo, Antonietta Arcella, Roberto Gradini, Amadeu Llebaria and Ferdinando Nicoletti
Int. J. Mol. Sci. 2022, 23(14), 8018; https://doi.org/10.3390/ijms23148018 - 20 Jul 2022
Cited by 2 | Viewed by 1973
Abstract
Breakthrough cancer pain (BTcP) refers to a sudden and transient exacerbation of pain, which develops in patients treated with opioid analgesics. Fast-onset analgesia is required for the treatment of BTcP. Light-activated drugs offer a novel potential strategy for the rapid control of pain [...] Read more.
Breakthrough cancer pain (BTcP) refers to a sudden and transient exacerbation of pain, which develops in patients treated with opioid analgesics. Fast-onset analgesia is required for the treatment of BTcP. Light-activated drugs offer a novel potential strategy for the rapid control of pain without the typical adverse effects of systemic analgesic drugs. mGlu5 metabotropic glutamate receptor antagonists display potent analgesic activity, and light-induced activation of one of these compounds (JF-NP-26) in the thalamus was found to induce analgesia in models of inflammatory and neuropathic pain. We used an established mouse model of BTcP based on the injection of cancer cells into the femur, followed, 16 days later, by systemic administration of morphine. BTcP was induced by injection of endothelin-1 (ET-1) into the tumor, 20 min after morphine administration. Mice were implanted with optic fibers delivering light in the visible spectrum (405 nm) in the thalamus or prelimbic cortex to locally activate systemically injected JF-NP-26. Light delivery in the thalamus caused rapid and substantial analgesia, and this effect was specific because light delivery in the prelimbic cortex did not relieve BTcP. This finding lays the groundwork for the use of optopharmacology in the treatment of BTcP. Full article
(This article belongs to the Special Issue Evolution of Cancer Pharmacological Treatment: Natural Compounds as Adjuvants for Cancer Treatments)
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Review

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27 pages, 1789 KiB  
Review
Natural Products for Esophageal Cancer Therapy: From Traditional Medicine to Modern Drug Discovery
by Jeongeun An, Soojin An, Min Choi, Ji Hoon Jung and Bonglee Kim
Int. J. Mol. Sci. 2022, 23(21), 13558; https://doi.org/10.3390/ijms232113558 - 04 Nov 2022
Cited by 5 | Viewed by 2836
Abstract
Esophageal cancer (EC) is one of the most malignant types of cancer worldwide and has a high incidence and mortality rate in Asian countries. When it comes to treating EC, although primary methods such as chemotherapy and surgery exist, the prognosis remains poor. [...] Read more.
Esophageal cancer (EC) is one of the most malignant types of cancer worldwide and has a high incidence and mortality rate in Asian countries. When it comes to treating EC, although primary methods such as chemotherapy and surgery exist, the prognosis remains poor. The purpose of this current research is to review the range of effects that natural products have on cancer by analyzing studies conducted on EC. Fifty-seven studies were categorized into four anti-cancer mechanisms, as well as clinical trials. The studies that were scrutinized in this research were all reported within five years. The majority of the substances reviewed induced apoptosis in EC, acting on a variety of mechanisms. Taken together, this study supports the fact that natural products have the potential to act as a candidate for treating EC. Full article
(This article belongs to the Special Issue Evolution of Cancer Pharmacological Treatment: Natural Compounds as Adjuvants for Cancer Treatments)
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Other

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13 pages, 860 KiB  
Case Report
Toxicity Derived from Interaction between Natural Compounds and Cancer Therapeutic Drugs Metabolized by CYP3A4: Lessons Learned from Two Clinical Case Reports
by Sabrina Orzetti and Paolo Baldo
Int. J. Mol. Sci. 2023, 24(21), 15976; https://doi.org/10.3390/ijms242115976 - 05 Nov 2023
Cited by 1 | Viewed by 1438
Abstract
The use of natural compounds and, in general, the use of Complementary and Alternative Medicine (CAM), is growing steadily worldwide, both due to commercial pressure and the increasing use of self-medication and the desire to manage one’s own personal health and well-being. Patients [...] Read more.
The use of natural compounds and, in general, the use of Complementary and Alternative Medicine (CAM), is growing steadily worldwide, both due to commercial pressure and the increasing use of self-medication and the desire to manage one’s own personal health and well-being. Patients facing a cancer diagnosis are also strongly pressured to use these compounds, which are often added to standard therapeutic regimens, that should instead be based solely on diagnostic and therapeutic care pathways (DTCP) or evidence-based medicine (EBM). This study presents two clinical cases of cancer patients who presented to the pharmaceutical consultation service (PCD—Pharmacy Clinical Desk) established at the CRO Institute in Aviano, Italy. Both patients were using natural products along with prescribed chemotherapy. In the first case, a 55-year-old woman diagnosed with bilateral breast cancer with bone metastases, who was using natural compounds based on diosmin, escin (or aescin) and resveratrol in combination with ribociclib anticancer therapy, a severe ADR (neutropenia) was identified as a consequence of the drug–natural product interaction. In the second case, following a detailed medication review by the PCD, we avoided taking a therapeutic treatment (with natural compounds) that in itself could potentially render chemotherapy ineffective in a 57-year-old woman with multiple infiltrating ductal carcinoma of the left breast; the patient was planning to take a natural product containing St. John’s Wort tincture and lemon balm tincture, in combination with paclitaxel and trastuzumab. In addition, we describe the corrective actions taken, thus outlining the main objectives of the activity of the PCD’s pharmacy counseling service: first, to identify, report, and manage adverse drug reactions (ADRs), and second, to identify therapeutic combinations that present potential risks of toxicity or ineffectiveness of the drug therapy itself. Full article
(This article belongs to the Special Issue Evolution of Cancer Pharmacological Treatment: Natural Compounds as Adjuvants for Cancer Treatments)
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