Editorial

3 pages, 181 KiB

Open AccessEditorial

Natural-Product-Inspired Approaches for Cancer Diagnosis and Therapy

by Eun Sook Lee and Jung Min Shin

Pharmaceutics 2022, 14(9), 1884; https://doi.org/10.3390/pharmaceutics14091884 - 06 Sep 2022

Viewed by 981

In recent years, new methods of cancer diagnosis and therapy have emerged as promising options for fighting cancer [...] Full article

(This article belongs to the Special Issue Natural Product-Inspired Approaches for Cancer Diagnosis and Therapy)

Research

Jump to: Editorial, Review

18 pages, 4470 KiB

Open AccessArticle

Immunomodulatory Effect of Hispolon on LPS-Induced RAW264.7 Cells and Mitogen/Alloantigen-Stimulated Spleen Lymphocytes of Mice

by Eun Kyeong Lee, Eun Mi Koh, Yu Na Kim, Jeongah Song, Chi Hun Song and Kyung Jin Jung

Pharmaceutics 2022, 14(7), 1423; https://doi.org/10.3390/pharmaceutics14071423 - 06 Jul 2022

Cited by 5 | Viewed by 2115

Abstract

Hispolon is a potent anticancer, anti-inflammatory, antioxidant, and antidiabetic agent isolated from Phellinus linteus, an oriental medicinal mushroom. However, the immunomodulatory mechanisms by which hispolon affects macrophages and lymphocytes remain poorly characterized. We investigated the immunomodulatory effects of hispolon on oxidative stress, [...] Read more.

Hispolon is a potent anticancer, anti-inflammatory, antioxidant, and antidiabetic agent isolated from Phellinus linteus, an oriental medicinal mushroom. However, the immunomodulatory mechanisms by which hispolon affects macrophages and lymphocytes remain poorly characterized. We investigated the immunomodulatory effects of hispolon on oxidative stress, inflammatory responses, and lymphocyte proliferation using lipopolysaccharide (LPS)-treated RAW264.7 macrophages or mitogen/alloantigen-treated mouse splenocytes. Hispolon inhibited LPS-induced reactive oxygen and nitrogen species (ROS/RNS) generation and decreased total sulfhydryl (SH) levels in a cell-free system and RAW264.7 cells. Hispolon exerted significant anti-inflammatory effects by inhibiting production of the proinflammatory cytokines interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α) and activation of nuclear factor kappa B (NF-κB) and signal transducer and activator of transcription 3 (STAT3) in LPS-treated RAW264.7 cells. Hispolon also modulated NF-κB and STAT3 activation by suppressing the NF-κB p65 interaction with phospho-IκBα and the STAT3 interaction with JAK1, as determined via coimmunoprecipitation analysis. Additionally, hispolon significantly decreased lymphocyte proliferation, T cell responses and T helper type 1 (Th1)/type 2 (Th2) cytokines production in mitogen/alloantigen-treated splenocytes. We conclude that hispolon exerts immunomodulatory effects on LPS-treated macrophages or mitogen/alloantigen-treated splenocytes through antioxidant, anti-inflammatory, and antiproliferative activities. Thus, hispolon may be a therapeutic agent for treating immune-mediated inflammatory diseases. Full article

(This article belongs to the Special Issue Natural Product-Inspired Approaches for Cancer Diagnosis and Therapy)

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23 pages, 3949 KiB

Open AccessArticle

Photothermal Therapy with HER2-Targeted Silver Nanoparticles Leading to Cancer Remission

by Victoria O. Shipunova, Mariia M. Belova, Polina A. Kotelnikova, Olga N. Shilova, Aziz B. Mirkasymov, Natalia V. Danilova, Elena N. Komedchikova, Rachela Popovtzer, Sergey M. Deyev and Maxim P. Nikitin

Pharmaceutics 2022, 14(5), 1013; https://doi.org/10.3390/pharmaceutics14051013 - 08 May 2022

Cited by 30 | Viewed by 2914

Abstract

Nanoparticles exhibiting the localized surface plasmon resonance (LSPR) phenomenon are promising tools for diagnostics and cancer treatment. Among widely used metal nanoparticles, silver nanoparticles (Ag NPs) possess the strongest light scattering and surface plasmon strength. However, the therapeutic potential of Ag NPs has [...] Read more.

Nanoparticles exhibiting the localized surface plasmon resonance (LSPR) phenomenon are promising tools for diagnostics and cancer treatment. Among widely used metal nanoparticles, silver nanoparticles (Ag NPs) possess the strongest light scattering and surface plasmon strength. However, the therapeutic potential of Ag NPs has until now been underestimated. Here we show targeted photothermal therapy of solid tumors with 35 nm HER2-targeted Ag NPs, which were produced by the green synthesis using an aqueous extract of Lavandula angustifolia Mill. Light irradiation tests demonstrated effective hyperthermic properties of these NPs, namely heating by 10 °C in 10 min. To mediate targeted cancer therapy, Ag NPs were conjugated to the scaffold polypeptide, affibody Z_HER2:342, which recognizes a clinically relevant oncomarker HER2. The conjugation was mediated by the PEG linker to obtain Ag-PEG-HER2 nanoparticles. Flow cytometry tests showed that Ag-PEG-HER2 particles successfully bind to HER2-overexpressing cells with a specificity comparable to that of full-size anti-HER2 IgGs. A confocal microscopy study showed efficient internalization of Ag-PEG-HER2 into cells in less than 2 h of incubation. Cytotoxicity assays demonstrated effective cell death upon exposure to Ag-PEG-HER2 and irradiation, caused by the production of reactive oxygen species. Xenograft tumor therapy with Ag-PEG-HER2 particles in vivo resulted in full primary tumor regression and the prevention of metastatic spread. Thus, for the first time, we have shown that HER2-directed plasmonic Ag nanoparticles are effective sensitizers for targeted photothermal oncotherapy. Full article

(This article belongs to the Special Issue Natural Product-Inspired Approaches for Cancer Diagnosis and Therapy)

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24 pages, 4026 KiB

Open AccessArticle

A Comparative Study on Inhibition of Breast Cancer Cells and Tumors in Mice by Carotenoid Extract and Nanoemulsion Prepared from Sweet Potato (Ipomoea batatas L.) Peel

by Hsin-Yen Hsu and Bing-Huei Chen

Pharmaceutics 2022, 14(5), 980; https://doi.org/10.3390/pharmaceutics14050980 - 02 May 2022

Cited by 11 | Viewed by 1952

Abstract

The objectives of this study were to determine carotenoid composition in sweet potato (TNG66) peel and prepare carotenoid nanoemulsion to study its inhibition effect on breast cancer cells MCF-7 and tumors in mice. Results showed that a total of 10 carotenoids were separated [...] Read more.

The objectives of this study were to determine carotenoid composition in sweet potato (TNG66) peel and prepare carotenoid nanoemulsion to study its inhibition effect on breast cancer cells MCF-7 and tumors in mice. Results showed that a total of 10 carotenoids were separated within 30 min by employing a YMC C30 column and a gradient mobile phase of methanol/acetonitrile/water (74:14:12, v/v/v) and dichloromethane (B) with a flow rate of 1 mL/min, column temperature of 25 °C, and detection wavelength of 450 nm. Following quantitation, all-trans-β-carotene was present in the highest amount (663.8 μg/g). The method validation data demonstrated a high accuracy and precision of this method. The carotenoid nanoemulsion was prepared by mixing an appropriate proportion of carotenoid extract, Tween 80, PEG 400, soybean oil and deionized water with the mean particle size being 15.7 nm (transmission electron microscope (TEM)), polydispersity index 0.238, encapsulation efficiency 97% and zeta potential −69.8 mV. A high stability of carotenoid nanoemulsion was shown over a 90-day storage period at 25 °C and during heating at 100 °C for 2 h. The release percentage of total carotenoids from carotenoid nanoemulsion under gastric and intestinal condition was 18.3% and 49.1%, respectively. An antiproliferation study revealed that carotenoid nanoemulsion was more effective than carotenoid extract in inhibiting the growth of human breast cancer cells MCF-7. Following treatments of paclitaxel (10 μg/mL), carotenoid nanoemulsion (20 and 10 μg/mL) and carotenoid extract (20 and 10 μg/mL), the tumor weight of mice respectively decreased by 77.4, 56.2, 40.3, 36.1 and 18.7%, as well as tumor volume of mice by 75.4, 65.0, 49.7, 46.7 and 26.5%. Also, both carotenoid extract and nanoemulsion could reduce the levels of epidermal growth factor (EGF) and (vascular endothelial growth factor (VEGF) in serum, with the latter being more effective. This finding suggested that carotenoid nanoemulsion was more effective than carotenoid extract in inhibiting tumor growth in mice. Full article

(This article belongs to the Special Issue Natural Product-Inspired Approaches for Cancer Diagnosis and Therapy)

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18 pages, 4295 KiB

Open AccessArticle

Impairment of Glucose Metabolism and Suppression of Stemness in MCF-7/SC Human Breast Cancer Stem Cells by Nootkatone

by Yen Thi-Kim Nguyen, Ngoc Bao To, Vi Nguyen-Phuong Truong, Hee Young Kim, Meran Keshawa Ediriweera, Yoongho Lim and Somi Kim Cho

Pharmaceutics 2022, 14(5), 906; https://doi.org/10.3390/pharmaceutics14050906 - 21 Apr 2022

Cited by 4 | Viewed by 2774

Abstract

Targeting cancer stem cell metabolism has emerged as a promising therapeutic strategy for cancer treatment. Breast cancer stem cells (BCSCs) exert distinct metabolism machinery, which plays a major role in radiation and multidrug resistance. Therefore, exploring the mechanisms involved in energy utilization of [...] Read more.

Targeting cancer stem cell metabolism has emerged as a promising therapeutic strategy for cancer treatment. Breast cancer stem cells (BCSCs) exert distinct metabolism machinery, which plays a major role in radiation and multidrug resistance. Therefore, exploring the mechanisms involved in energy utilization of BCSCs could improve the effectiveness of therapeutic strategies aimed at their elimination. This study was conducted to clarify the glucose metabolism machinery and the function of nootkatone, a bioactive component of grapefruit, in regulating glucose metabolism and stemness characteristics in human breast carcinoma MCF-7 stem cells (MCF-7SCs). In vivo experiments, transcriptomic analysis, seahorse XF analysis, MTT assay, Western blotting, mammosphere formation, wound healing, invasion assay, flow cytometric analysis, reverse transcription-quantitative polymerase chain reaction, and in silico docking experiments were performed. MCF-7SCs showed a greater tumorigenic capacity and distinct gene profile with enrichment of the genes involved in stemness and glycolysis signaling pathways compared to parental MCF-7 cells, indicating that MCF-7SCs use glycolysis rather than oxidative phosphorylation (OXPHOS) for their energy supply. Nootkatone impaired glucose metabolism through AMPK activation and reduced the stemness characteristics of MCF-7SCs. In silico docking analysis demonstrated that nootkatone efficiently bound to the active site of AMPK. Therefore, this study indicates that regulation of glucose metabolism through AMPK activation could be an attractive target for BCSCs. Full article

(This article belongs to the Special Issue Natural Product-Inspired Approaches for Cancer Diagnosis and Therapy)

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24 pages, 9159 KiB

Open AccessArticle

Honeybee Venom Synergistically Enhances the Cytotoxic Effect of CNS Drugs in HT-29 Colon and MCF-7 Breast Cancer Cell Lines

by Diana Duarte, Soraia I. Falcão, Iouraouine El Mehdi, Miguel Vilas-Boas and Nuno Vale

Pharmaceutics 2022, 14(3), 511; https://doi.org/10.3390/pharmaceutics14030511 - 25 Feb 2022

Cited by 18 | Viewed by 3763

Abstract

5-fluorouracil (5-FU) and doxorubicin (DOX) are potent anti-tumour agents commonly used for colon and breast cancer therapy, respectively. However, their clinical application is limited by their side effects and the development of drug resistance. Honeybee venom is a complex mixture of substances that [...] Read more.

5-fluorouracil (5-FU) and doxorubicin (DOX) are potent anti-tumour agents commonly used for colon and breast cancer therapy, respectively. However, their clinical application is limited by their side effects and the development of drug resistance. Honeybee venom is a complex mixture of substances that has been reported to be effective against different cancer cells. Its active compound is melittin, a positively charged amphipathic peptide that interacts with the phospholipids of the cell membrane, forming pores that enable the internalization of small molecules with cytotoxic activities,^. and consequently, causing cell death. Some central nervous system (CNS) drugs have recently demonstrated great anti-cancer potential, both in vitro, in vivo and in clinical trials, being promising candidates for drug repurposing in oncology. The present work evaluated the anti-cancer efficacy of honeybee venom in combination with chemotherapeutic or CNS drugs in HT-29 colon and MCF-7 breast cancer cell lines. The chemical characterization of a Portuguese sample of honeybee venom was done by LC-DAD-ESI/MSn analysis. For single treatments, cells were incubated with increasing concentrations of bee venom. For combination treatments, increasing concentrations of bee venom were first combined with the half-maximal inhibitory concentration (IC₅₀) of 5-FU and DOX, in HT-29 and MCF-7 cells, respectively. Cells were also treated with increasing concentrations of bee venom in combination with the IC₅₀ value of four CNS drugs (fluphenazine, fluoxetine, sertraline and thioridazine). Cytotoxicity was evaluated by MTT and SRB assays. The combination index (CI) value was calculated using CompuSyn software, based on the Chou–Talalay method. Synergy scores of different reference models (HSA, Loewe, ZIP and Bliss) were also calculated using SynergyFinder. The results demonstrate that honeybee venom is active against HT-29 colon and MCF-7 breast cancer cells, having better anti-tumour activity in MCF-7 cells. It was found that bee venom combined with 5-FU and fluphenazine in HT-29 cells resulted in less cytotoxic effects compared to the co-treatment of fluoxetine, sertraline and thioridazine plus bee venom, which resulted in less than 15% of viable cells for the whole range of concentrations. The combination of MCF-7 cells with repurposed drugs plus honeybee venom resulted in better anti-cancer efficacies than with DOX, notably for lower concentrations. A combination of fluoxetine and thioridazine plus honeybee venom resulted in less than 40% of viable cells for all ranges of concentrations. These results support that the combination of honeybee venom with repurposed drugs and chemotherapeutic agents can help improve their anti-cancer activity, especially for lower concentrations, in both cell lines. Overall, the present study corroborates the enormous bioactive potential of honeybee venom for colon and breast cancer treatments, both alone and in combination with chemotherapy or repurposed drugs. Full article

(This article belongs to the Special Issue Natural Product-Inspired Approaches for Cancer Diagnosis and Therapy)

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13 pages, 4088 KiB

Open AccessArticle

Eradication of Myrosinase-Tethered Cancer Cells by Allyl Isothiocyanate Derived from Enzymatic Hydrolysis of Sinigrin

by Ammar Tarar, Esmael M. Alyami and Ching-An Peng

Pharmaceutics 2022, 14(1), 144; https://doi.org/10.3390/pharmaceutics14010144 - 07 Jan 2022

Cited by 6 | Viewed by 2308

Abstract

Sinigrin is present in significant amounts in cruciferous vegetables. Epidemiological studies suggest that the consumption of such vegetables decreases the risk of cancer, and the effect is attributed mainly to allyl isothiocyanate (AITC), a hydrolysis product of sinigrin catalyzed by myrosinase. Anticancer activity [...] Read more.

Sinigrin is present in significant amounts in cruciferous vegetables. Epidemiological studies suggest that the consumption of such vegetables decreases the risk of cancer, and the effect is attributed mainly to allyl isothiocyanate (AITC), a hydrolysis product of sinigrin catalyzed by myrosinase. Anticancer activity of AITC has been previously investigated for several cancer models, but less attention was paid to delivering AITC on the target site. In this study, the gene sequences of core streptavidin (coreSA) and myrosinase (MYR) were cloned in a pET-30a(+) plasmid and transformed into BL21(DE3) E. coli competent cells. The MYR-coreSA chimeric protein was expressed and purified using immobilized metal affinity chromatography and further characterized by gel electrophoresis, Western blot, and enzyme activity assay. The purified MYR-coreSA chimeric protein was tethered on the outer membrane of biotinylated adenocarcinoma A549 cells and then treated with various concentrations of sinigrin. Our results showed that 20 µM of sinigrin inhibited the growth of A549 cells tethered with myrosinase by ~60% in 48 h. Furthermore, the levels of treated cells undertaken apoptosis were determined by Caspase-3/7 activation and Annexin-V. In summary, sinigrin harnessed like a prodrug catalyzed by myrosinase to the production of AITC, which induced cell apoptosis and arrested the growth of lung cancer cells. Full article

(This article belongs to the Special Issue Natural Product-Inspired Approaches for Cancer Diagnosis and Therapy)

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19 pages, 16996 KiB

Open AccessArticle

Comparative Study on Inhibition of Pancreatic Cancer Cells by Resveratrol Gold Nanoparticles and a Resveratrol Nanoemulsion Prepared from Grape Skin

by Baskaran Stephen Inbaraj, Leng-Huei Hua and Bing-Huei Chen

Pharmaceutics 2021, 13(11), 1871; https://doi.org/10.3390/pharmaceutics13111871 - 05 Nov 2021

Cited by 13 | Viewed by 1859

Abstract

Resveratrol, a phenolic compound possessing vital biological activities such as anti-cancer, is present abundantly in grape skin, a waste produced during the processing of grape juice. The objectives of this study were to prepare resveratrol-gold nanoparticles and a resveratrol nanoemulsion from grape skin [...] Read more.

Resveratrol, a phenolic compound possessing vital biological activities such as anti-cancer, is present abundantly in grape skin, a waste produced during the processing of grape juice. The objectives of this study were to prepare resveratrol-gold nanoparticles and a resveratrol nanoemulsion from grape skin and study their inhibition effects on pancreatic cancer cells BxPC-3. The spherical-shaped citrate gold nanoparticles (GNPs) and resveratrol-gold nanoparticles (R-GNPs) were, respectively, prepared with a surface plasmon resonance peak at 528 and 538 nm, mean particle size of 20.8 and 11.9 nm, and zeta-potential at −32.7 and −66.7 mV, by controlling an appropriate concentration of citrate/resveratrol and gold chloride as well as stirring time and temperature. The resveratrol nanoemulsion, composed of soybean oil, Tween 80, and sucrose fatty acid ester in glycerol and water, possessed a high storage stability with a mean particle size of 14.1 nm, zeta-potential of −49.7 mV, and encapsulation efficiency of 95.5%. An antiproliferation study revealed that both R-GNPs and resveratrol nanoemulsion could effectively inhibit the growth of pancreatic cancer cells BxPC-3, with the latter showing a higher inhibition effect. Western blot analysis implied that both can down-regulate expressions of cyclin A, cyclin B, CDK1, and CDK2 and up-regulate expressions of p53 and p21, accompanied by enhancing cytochrome C expression, decreasing BcL-2 expression, increasing Bax expression, and leading to the elevation of caspase-8, caspase-9, and caspase-3 activities for cell apoptosis execution. Future research is needed to study the inhibition of pancreatic tumors in vivo by R-GNPs and resveratrol nanoemulsions. Full article

(This article belongs to the Special Issue Natural Product-Inspired Approaches for Cancer Diagnosis and Therapy)

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26 pages, 6386 KiB

Open AccessArticle

Identification of Effective Anticancer G-Quadruplex-Targeting Chemotypes through the Exploration of a High Diversity Library of Natural Compounds

by Chiara Platella, Francesca Ghirga, Pasquale Zizza, Luca Pompili, Simona Marzano, Bruno Pagano, Deborah Quaglio, Valeria Vergine, Silvia Cammarone, Bruno Botta, Annamaria Biroccio, Mattia Mori and Daniela Montesarchio

Pharmaceutics 2021, 13(10), 1611; https://doi.org/10.3390/pharmaceutics13101611 - 03 Oct 2021

Cited by 13 | Viewed by 2041

Abstract

In the quest for selective G-quadruplex (G4)-targeting chemotypes, natural compounds have been thus far poorly explored, though representing appealing candidates due to the high structural diversity of their scaffolds. In this regard, a unique high diversity in-house library composed of ca. one thousand [...] Read more.

In the quest for selective G-quadruplex (G4)-targeting chemotypes, natural compounds have been thus far poorly explored, though representing appealing candidates due to the high structural diversity of their scaffolds. In this regard, a unique high diversity in-house library composed of ca. one thousand individual natural products was investigated. The combination of molecular docking-based virtual screening and the G4-CPG experimental screening assay proved to be useful to quickly and effectively identify—out of many natural compounds—five hit binders of telomeric and oncogenic G4s, i.e., Bulbocapnine, Chelidonine, Ibogaine, Rotenone and Vomicine. Biophysical studies unambiguously demonstrated the selective interaction of these compounds with G4s compared to duplex DNA. The rationale behind the G4 selective recognition was suggested by molecular dynamics simulations. Indeed, the selected ligands proved to specifically interact with G4 structures due to peculiar interaction patterns, while they were unable to firmly bind to a DNA duplex. From biological assays, Chelidonine and Rotenone emerged as the most active compounds of the series against cancer cells, also showing good selectivity over normal cells. Notably, the anticancer activity correlated well with the ability of the two compounds to target telomeric G4s. Full article

(This article belongs to the Special Issue Natural Product-Inspired Approaches for Cancer Diagnosis and Therapy)

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Review

Jump to: Editorial, Research

15 pages, 716 KiB

Open AccessReview

Reptiles as Promising Sources of Medicinal Natural Products for Cancer Therapeutic Drugs

by Soon Yong Park, Hyeongrok Choi and Jin Woong Chung

Pharmaceutics 2022, 14(4), 874; https://doi.org/10.3390/pharmaceutics14040874 - 16 Apr 2022

Cited by 4 | Viewed by 2193

Abstract

Natural products have historically played an important role as a source of therapeutic drugs for various diseases, and the development of medicinal natural products is still a field with high potential. Although diverse drugs have been developed for incurable diseases for several decades, [...] Read more.

Natural products have historically played an important role as a source of therapeutic drugs for various diseases, and the development of medicinal natural products is still a field with high potential. Although diverse drugs have been developed for incurable diseases for several decades, discovering safe and efficient anticancer drugs remains a formidable challenge. Reptiles, as one source of Asian traditional medicines, are known to possess anticancer properties and have been used for a long time without a clarified scientific background. Recently, it has been reported that extracts, crude peptides, sera, and venom isolated from reptiles could effectively inhibit the survival and proliferation of various cancer cells. In this article, we summarize recent studies applying ingredients derived from reptiles in cancer therapy and discuss the difficulties and prospective development of natural product research. Full article

(This article belongs to the Special Issue Natural Product-Inspired Approaches for Cancer Diagnosis and Therapy)

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