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Bioactive Phytochemicals for Cancer Prevention and Treatment

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

Deadline for manuscript submissions: closed (31 August 2019) | Viewed by 71472

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Special Issue Editors

Prof. Dr. Sanjay K. Srivastava

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Department of Immunotherapeutics and Biotechnology, Texas Tech University Health Sciences Center, 1718 Pine Street, Abilene, TX 79601, USA
Interests: development of phytochemicals for cancer prevention and therapeutics; targeting STAT-3, NF-kB, HER2, MCL-1, AKT/FOXO, GLI1/2, and related signaling pathways with agents such as capsaicin, piperlongumine, penfluridol, isothiocyanates, diindolylmethane, panabinostat, cucurbitacin B, and deguelin in pancreatic, ovarian, breast, melanoma, and brain cancer; drug repurposing
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Prof. Dr. Sung-Hoon Kim

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Cancer Molecular Target Herbal Research Lab, College of Korean Medicine, Kyunghee University, Seoul 02447, Republic of Korea
Interests: cancer biology; oriental prescriptions; herbal extracts; natural compounds; inflammation; cancer; Immune; thrombosis; biological activity
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Plants have been an important source of bioactive phytochemicals since historic times. Phytochemicals are synthesized by plants as their defensive mechanisms. Several epidemiological studies indicate an inverse correlation between the intake of specific plant foods and cancer incidence. Thousands of phytochemicals have been identified to date, but only a few have been explored in depth for their beneficial roles. Phytochemicals available from dietary plant sources can be classified based on their chemical structures. For example, isothiocyanates, indoles, carotenoids, flavonoids, isoflavones, and terpenoids are some of the major classes studied for their anti-cancer effects. Phytochemicals are considered to be advantageous over the current chemotherapeutic options available. This is because cancer etiology involves multiple mechanisms, and phytochemicals, being pleiotropic, can counter more pro-carcinogenic mechanisms. Moreover, being a component of dietary plants, phytochemicals are also relatively non-toxic and generally have broader safety windows. Combination therapy is evitable in clinical practice. Several phytochemicals have been shown to enhance the effects of chemotherapeutic drugs. This Special Issue has been envisaged to document studies on well-known phytochemicals and their role in cancer prevention. The articles in this Issue are contributed by eminent researchers in the field of cancer chemoprevention, from all around the world. This Issue will be beneficial to all the basic, clinical, and applied researchers and physicians interested in cancer chemoprevention and chemotherapeutics.

Prof. Dr. Sanjay K. Srivastava
Prof. Dr. Sung-Hoon Kim
Guest Editors

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Keywords

cancer
chemoprevention
phytochemicals
dietary agents
functional foods
bioactive agents
anti-cancer
molecular mechanism
signaling mechanism
cell cycle
apoptosis
combination therapy
therapeutics

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Published Papers (13 papers)

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12 pages, 3971 KiB

Open AccessArticle

Farnesiferol C Induces Apoptosis in Chronic Myelogenous Leukemia Cells as an Imatinib Sensitizer via Caspase Activation and HDAC (Histone Deacetylase) Inactivation

by Ji Hoon Jung, Ji Eon Park, Deok Yong Sim, Eunji Im, Woon Yi Park, Duckgue Lee, Bum-Sang Shim and Sung-Hoon Kim

Int. J. Mol. Sci. 2019, 20(22), 5535; https://doi.org/10.3390/ijms20225535 - 6 Nov 2019

Cited by 3 | Viewed by 2805

Abstract

Herein the underlying apoptotic mechanism of Farnesiferol C (FC) derived from Ferula assafoetida was elucidated in chronic myelogenous leukemia (CML) K562 and KBM5 cells. FC showed significant cytotoxicity in K562 and KBM5 cells, more so than in U937 and UL-60 acute myeloid leukemia (AML) cells. Cleaved PARP and caspase 9/3 attenuated the expression of Bcl2 and induced G1 arrest in K562 and KBM5 cells. Also, FC effectively abrogated the expression of cell cycle related proteins, such as: Cyclin D1, Cyclin E, Cyclin B1 in K562, and KBM5 cells, but caspase 3 inhibitor Z-DEVD-FMK rescued the cleavages of caspase 3 and PARP induced by FC in K562 cells. Of note, FC decreased histone deacetylase 1 (HDAC1) and HDAC2, and enhanced histone H3 acetylation K18 (Ac-H3K18) in K562 and KBM5 cells. Furthermore, combination of FC and Imatinib enhanced the apoptotic effect of Imatinib as a potent Imatinib sensitizer in K562 cells. Overall, our findings provide scientific evidence that inactivation of HDAC and caspase activation mediate FC induced apoptosis in CML cells. Full article

(This article belongs to the Special Issue Bioactive Phytochemicals for Cancer Prevention and Treatment)

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15 pages, 3957 KiB

Open AccessArticle

A Novel Paclitaxel Conjugate with Higher Efficiency and Lower Toxicity: A New Drug Candidate for Cancer Treatment

by Mizied Falah, Mahmoud Rayan and Anwar Rayan

Int. J. Mol. Sci. 2019, 20(19), 4965; https://doi.org/10.3390/ijms20194965 - 8 Oct 2019

Cited by 18 | Viewed by 5329

Abstract

Paclitaxel-lipoate (IDD-1040) is a conjugate formed by the chemical joining of the two compounds, by condensing a lipoic acid moiety to the C2′ of paclitaxel. IDD-1040 was evaluated for its anti-tumor activity and potential druggability, using an in vivo non-small-cell, lung cancer (NSCLC) xenograft mouse model. In the in vivo studies, IDD-1040 showed a maximum tolerated dose (MTD) of 250 mg/kg compared to paclitaxel (PTX), with an MTD of 20 mg/kg. Most interesting, IDD-1040 demonstrated higher anti-tumor activity, and its inhibitory activity on tumor volume (cell growth) was dose-dependent. That anti-tumor activity persisted for two weeks after cessation of IDD-1040 treatment, as opposed to PTX cessation, after which the tumor relapsed, confirming that IDD-1040 exhibits superior tumor inhibition. Similar to PTX treatment, no marked body weight decrease was observed during IDD-1040 treatment, indicating a low toxicity profile. The increase in animal body weight noted over time was due to the increasing weight of tumors, recorded in all the mouse test groups. The results also showed that mortality rate of mice was reduced by treatment with IDD-1040, more so than with PTX. Furthermore, in a preliminary study on the ex vivo distribution of IDD-1040, neutropenia was primarily concentrated in the liver 1 h after injection, and most of the drug was metabolized by the liver in 24 h. All of these results demonstrate IDD-1040’s great potential as a candidate drug for cancer treatment. Full article

(This article belongs to the Special Issue Bioactive Phytochemicals for Cancer Prevention and Treatment)

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16 pages, 2975 KiB

Open AccessArticle

Curcumin-Gene Expression Response in Hormone Dependent and Independent Metastatic Prostate Cancer Cells

by Shilpa Katta, Arun Srivastava, Rajesh L. Thangapazham, Inger L. Rosner, Jennifer Cullen, Hua Li and Shashwat Sharad

Int. J. Mol. Sci. 2019, 20(19), 4891; https://doi.org/10.3390/ijms20194891 - 2 Oct 2019

Cited by 32 | Viewed by 6182

Abstract

The androgen receptor is one of the key targets for prostate cancer treatment. Despite its less satisfactory effects, chemotherapy is the most common treatment option for metastatic and/or castration-resistant patients. There are constant needs for novel anti-prostate cancer therapeutic/prevention agents. Curcumin, a known chemo-preventive agent, was shown to inhibit prostate cancer cell growth. This study aimed to unravel the inhibitory effect of curcumin in prostate cancer through analyzing the alterations of expressions of curcumin targeting genes clusters in androgen-dependent LNCaP cells and androgen-independent metastatic C4-2B cells. Hierarchical clustering showed the highest number of differentially expressed genes at 12 h post treatment in both cells, suggesting that the androgen-dependent/independent manner of curcumin impacts on prostate cancer cells. Evaluation of significantly regulated top canonical pathways highlighted that Transforming growth factor beta (TGF-β), Wingless-related integration site (Wnt), Phosphoinositide 3-kinase/Protein Kinase B/ mammalian target of rapamycin (PIK3/AKT(PKB)/mTOR), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) signaling were primarily inhibited, and Phosphatase and tensin homolog (PTEN) dependent cell cycle arrest and apoptosis pathways were elevated with curcumin treatment. The short term (3–24 h) and long term (48 h) effect of curcumin treatment revealed 31 and four genes modulated in both cell lines. TGF-β signaling, including the androgen/TGF-β inhibitor Prostate transmembrane protein androgen-induced 1 (PMEPA1), was the only pathway impacted by curcumin treatment after 48 h. Our findings also established that MYC Proto-Oncogene, basic helix-loop-helix (bHLH) Transcription Factor (MYC) signaling was down-regulated in curcumin-treated cell lines. This study established, for the first time, novel gene-networks and signaling pathways confirming the chemo-preventive and cancer-growth inhibitory nature of curcumin as a natural anti-prostate cancer compound. Full article

(This article belongs to the Special Issue Bioactive Phytochemicals for Cancer Prevention and Treatment)

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16 pages, 3976 KiB

Open AccessArticle

Quercetin Enhances the Anti-Tumor Effects of BET Inhibitors by Suppressing hnRNPA1

by Thao N.D. Pham, Sophie Stempel, Mario A. Shields, Christina Spaulding, Krishan Kumar, David J. Bentrem, Maria Matsangou and Hidayatullah G. Munshi

Int. J. Mol. Sci. 2019, 20(17), 4293; https://doi.org/10.3390/ijms20174293 - 2 Sep 2019

Cited by 39 | Viewed by 4621

Abstract

Bromodomain and extraterminal domain (BET) proteins, which are important epigenetic readers, are often dysregulated in cancer. While a number of BET inhibitors are currently in early phase clinical trials, BET inhibitors show limited single-agent activity. The purpose of this study is to determine if Quercetin, a naturally occurring polyphenolic flavonoid often found abundant in fruits and vegetables, can enhance the anti-tumor effects of BET inhibitors. The efficacy of the combination was evaluated in vitro and in a xenograft model of pancreatic cancer. Co-treatment with BET inhibitors and Quercetin promoted apoptosis, decreased sphere-forming ability by cancer cells, and decreased cell proliferation. We found that hnRNPA1, a nuclear protein known to control mRNA export and mRNA translation of anti-apoptotic proteins, mediates some anti-tumor effects by Quercetin. Additionally, we show that combining BET inhibitors with Quercetin or hnRNPA1 knockdown decreased the anti-apoptotic protein Survivin. Significantly, Quercetin decreased hnRNPA1 in vivo and enhanced the effects of BET inhibitors at suppressing tumor growth. Together, these results demonstrate that Quercetin enhances the efficacy of BET inhibitors by suppressing hnRNPA1, and identify combination therapy with Quercetin and BET inhibitors for the treatment of cancer patients. Full article

(This article belongs to the Special Issue Bioactive Phytochemicals for Cancer Prevention and Treatment)

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16 pages, 5247 KiB

Open AccessArticle

Anti-Proliferative and Pro-Apoptotic Effects of Licochalcone A through ROS-Mediated Cell Cycle Arrest and Apoptosis in Human Bladder Cancer Cells

by Su Hyun Hong, Hee-Jae Cha, Hyun Hwang-Bo, Min Yeong Kim, So Young Kim, Seon Yeong Ji, JaeHun Cheong, Cheol Park, Hyesook Lee, Gi-Young Kim, Sung-Kwon Moon, Seok Joong Yun, Young-Chae Chang, Wun-Jae Kim and Yung Hyun Choi

Int. J. Mol. Sci. 2019, 20(15), 3820; https://doi.org/10.3390/ijms20153820 - 5 Aug 2019

Cited by 53 | Viewed by 5372

Abstract

Licochalcone A (LCA) is a chalcone that is predominantly found in the root of Glycyrrhiza species, which is widely used as an herbal medicine. Although previous studies have reported that LCA has a wide range of pharmacological effects, evidence for the underlying molecular mechanism of its anti-cancer efficacy is still lacking. In this study, we investigated the anti-proliferative effect of LCA on human bladder cancer cells, and found that LCA induced cell cycle arrest at G2/M phase and apoptotic cell death. Our data showed that LCA inhibited the expression of cyclin A, cyclin B1, and Wee1, but increased the expression of cyclin-dependent kinase (Cdk) inhibitor p21WAF1/CIP1, and increased p21 was bound to Cdc2 and Cdk2. LCA activated caspase-8 and -9, which are involved in the initiation of extrinsic and intrinsic apoptosis pathways, respectively, and also increased caspase-3 activity, a typical effect caspase, subsequently leading to poly (ADP-ribose) polymerase cleavage. Additionally, LCA increased the Bax/Bcl-2 ratio, and reduced the integrity of mitochondria, which contributed to the discharge of cytochrome c from the mitochondria to the cytoplasm. Moreover, LCA enhanced the intracellular levels of reactive oxygen species (ROS); however, the interruption of ROS generation using ROS scavenger led to escape from LCA-mediated G2/M arrest and apoptosis. Collectively, the present data indicate that LCA can inhibit the proliferation of human bladder cancer cells by inducing ROS-dependent G2/M phase arrest and apoptosis. Full article

(This article belongs to the Special Issue Bioactive Phytochemicals for Cancer Prevention and Treatment)

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14 pages, 2675 KiB

Open AccessArticle

Blockade of STAT3 Signaling Contributes to Anticancer Effect of 5-Acetyloxy-6,7,8,4′-Tetra-Methoxyflavone, a Tangeretin Derivative, on Human Glioblastoma Multiforme Cells

by Yen-Po Cheng, Shiming Li, Wan-Ling Chuang, Chia-Hsuan Li, Guan-Jun Chen, Ching-Chin Chang, Chi-Hung R. Or, Ping-Yi Lin and Chia-Che Chang

Int. J. Mol. Sci. 2019, 20(13), 3366; https://doi.org/10.3390/ijms20133366 - 9 Jul 2019

Cited by 22 | Viewed by 4871

Abstract

Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor with poor prognosis, largely due to resistance to current radiotherapy and Temozolomide chemotherapy. The constitutive activation of Signal Transducer and Activator of Transcription 3 (STAT3) is evidenced as a pivotal driver of GBM pathogenesis and therapy resistance, and hence, is a promising GBM drug target. 5-acetyloxy-6,7,8,4′-tetramethoxyflavone (5-AcTMF) is an acetylated derivative of Tangeretin which is known to exert anticancer effects on breast, colon, lung, and multiple myeloma; however, its effect on GBM remains elusive. Herein, we reported that 5-AcTMF suppressed the viability and clonogenicity along with inducing apoptosis in multiple human GBM cell lines. Mechanistic analyses further revealed that 5-AcTMF lowered the levels of Tyrosine 705-phosphorylated STAT3 (p-STAT3), a canonical marker of STAT3 activation, but also dampened p-STAT3 upregulation elicited by Interleukin-6. Notably, ectopic expression of dominant-active STAT3 impeded 5-AcTMF-induced suppression of viability and clonogenicity plus apoptosis induction in GBM cells, confirming the prerequisite of STAT3 blockage for the inhibitory action of 5-AcTMF on GBM cell survival and growth. Additionally, 5-AcTMF impaired the activation of STAT3 upstream kinase JAK2 but also downregulated antiapoptotic BCL-2 and BCL-xL in a STAT3-dependent manner. Moreover, the overexpression of either BCL-2 or BCL-xL abrogated 5-AcTMF-mediated viability reduction and apoptosis induction in GBM cells. Collectively, we, for the first time, revealed the anticancer effect of 5-AcTMF on GBM cells, which was executed via thwarting the JAK2-STAT3-BCL-2/BCL-xL signaling axis. Our findings further implicate the therapeutic potential of 5-AcTMF for GBM treatment. Full article

(This article belongs to the Special Issue Bioactive Phytochemicals for Cancer Prevention and Treatment)

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14 pages, 2506 KiB

Open AccessArticle

Suppression of STAT3 Phosphorylation and RelA/p65 Acetylation Mediated by MicroRNA134 Plays a Pivotal Role in the Apoptotic Effect of Lambertianic Acid

by Deok Yong Sim, Hyo-Jung Lee, Ji Hoon Jung, Eunji Im, Jisung Hwang, Dong Sub Kim and Sung-Hoon Kim

Int. J. Mol. Sci. 2019, 20(12), 2993; https://doi.org/10.3390/ijms20122993 - 19 Jun 2019

Cited by 11 | Viewed by 4968

Abstract

As p300-mediated RelA/p65 hyperacetylation by signal transducers and activators of transcription 3 (STAT3) is critical for NF-κB activation, in the current study, the apoptotic mechanism of lambertianic acid (LA) was explored in relation to STAT3 phosphorylation and RelA/p65 acetylation in MCF-7, DU145, PC-3, and MDA-MB-453 cells. LA significantly increased the cytotoxicity, sub G 1 population, and the cleavage of poly (ADP-ribose) polymerase (PARP) in MDA-MB-453 or PC-3 cells (STAT3 mutant), more than in the MCF-7 or DU145 cells (STAT3 wild). Consistently, LA inhibited the phosphorylation of STAT3 and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and disrupted the interaction between p-STAT3, p300, NF-κB, and RelA/p65 acetylation (Ac-RelA/p65) in the MCF-7 and DU145 cells. Also, LA reduced the nuclear translocation of STAT3 and NF-κB via their colocalization, and also suppressed the protein expression of XIAP, survivin, Bcl-2, Bcl-xL, vascular endothelial growth factor (VEGF), Cox-2, c-Myc and mRNA expression of interleukin 6 (IL-6), and tumor necrosis factor-α (TNF-α) in MCF-7 cells. Conversely, IL-6 blocked the ability of LA to suppress the cytotoxicity and PARP cleavage, while the depletion of STAT3 or p300 enhanced the PARP cleavage of LA in the MCF-7 cells. Notably, LA upregulated the level of miRNA134 and so miRNA134 mimic attenuated the expression of pro-PARP, p-STAT3, and Ac-RelA, while the miRNA134 inhibitor reversed the ability of LA to reduce the expression of Ac-RelA and pro-PARP in MCF-7 cells. Overall, these findings suggest that LA induced apoptosis via the miRNA-134 mediated inhibition of STAT3 and RelA/p65 acetylation. Full article

(This article belongs to the Special Issue Bioactive Phytochemicals for Cancer Prevention and Treatment)

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12 pages, 1010 KiB

Open AccessArticle

Synthesis and In Vitro Antitumor Activity of Naringenin Oxime and Oxime Ether Derivatives

by Ahmed Dhahir Latif, Tímea Gonda, Máté Vágvölgyi, Norbert Kúsz, Ágnes Kulmány, Imre Ocsovszki, Zoltán Péter Zomborszki, István Zupkó and Attila Hunyadi

Int. J. Mol. Sci. 2019, 20(9), 2184; https://doi.org/10.3390/ijms20092184 - 2 May 2019

Cited by 30 | Viewed by 5018

Abstract

Naringenin is one of the most abundant dietary flavonoids exerting several beneficial biological activities. Synthetic modification of naringenin is of continuous interest. During this study our aim was to synthesize a compound library of oxime and oxime ether derivatives of naringenin, and to investigate their biological activities. Two oximes and five oxime ether derivatives were prepared; their structure has been elucidated by NMR and high-resolution mass spectroscopy. The antiproliferative activity of the prepared compounds was evaluated by MTT assay against human leukemia (HL-60) and gynecological cancer cell lines isolated from cervical (HeLa, Siha) and breast (MCF-7, MDA-MB-231) cancers. Tert-butyl oxime ether derivative exerted the most potent cell growth inhibitory activity. Moreover, cell cycle analysis suggested that this derivative caused a significant increase in the hypodiploid (subG1) phase and induced apoptosis in Hela and Siha cells, and induced cell cycle arrest at G2/M phase in MCF-7 cells. The proapoptotic potential of the selected compound was confirmed by the activation of caspase-3. Antioxidant activities of the prepared molecules were also evaluated with xanthine oxidase, DPPH and ORAC assays, and the methyl substituted oxime ether exerted the most promising activity. Full article

(This article belongs to the Special Issue Bioactive Phytochemicals for Cancer Prevention and Treatment)

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14 pages, 2764 KiB

Open AccessArticle

Moringin from Moringa Oleifera Seeds Inhibits Growth, Arrests Cell-Cycle, and Induces Apoptosis of SH-SY5Y Human Neuroblastoma Cells through the Modulation of NF-κB and Apoptotic Related Factors

by Santa Cirmi, Nadia Ferlazzo, Agnese Gugliandolo, Laura Musumeci, Emanuela Mazzon, Alessia Bramanti and Michele Navarra

Int. J. Mol. Sci. 2019, 20(8), 1930; https://doi.org/10.3390/ijms20081930 - 19 Apr 2019

Cited by 62 | Viewed by 6292

Abstract

In the last decades, glucosinolates (GLs), precursors of isothiocyanates (ITCs), have been studied mostly for their chemopreventive and chemotherapeutic properties. The aim of our research was to study the antiproliferative effect of 4-(α-L-rhamnopyranosyloxy) benzyl glucosinolate (glucomoringin; GMG) bioactivated by myrosinase enzyme to form the corresponding isothiocyanate 4-(α-L-rhamnopyranosyloxy) benzyl C (moringin) in SH-SY5Y human neuroblastoma cells. We found that moringin significantly reduced SH-SY5Y cell growth in a time and concentration-dependent (p < 0.05, 0.01, and 0.001 vs. ctrl, after treatment with 16.4 µM moringin for 24, 48, and 72 h, respectively) manner through a mechanism involving the activation of apoptotic machinery. In addition, it altered the normal progression of cells through the cell cycle, increasing the cell population in both G2 and S phases, as well as decreasing that in the G1 phase. Studying the drug mechanism of action, we found that moringin was able to increase the expression of p53, p21, and Bax at both the protein and transcriptional level. Moreover, exposure of SH-SY5Y cells to moringin significantly increased the gene expression of both caspase 3 and 9 and enhanced their cleavage, thereby initiating an intrinsic apoptotic cascade. Finally, moringin inhibited nuclear translocation of NF-κB. Our study demonstrates the ability of moringin to reduce the growth of SH-SY5Y cells and reveals its mechanism of action, suggesting its promising role as an anticancer drug. Full article

(This article belongs to the Special Issue Bioactive Phytochemicals for Cancer Prevention and Treatment)

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12 pages, 1911 KiB

Open AccessCommunication

Antiproliferative and Cytotoxic Activity of Xanthohumol and Its Non-Estrogenic Derivatives in Colon and Hepatocellular Carcinoma Cell Lines

by Isabelle E. Logan, Cristobal L. Miranda, Malcolm B. Lowry, Claudia S. Maier, Jan F. Stevens and Adrian F. Gombart

Int. J. Mol. Sci. 2019, 20(5), 1203; https://doi.org/10.3390/ijms20051203 - 9 Mar 2019

Cited by 38 | Viewed by 9388

Abstract

Xanthohumol (XN), a prenylated flavonoid found in hops, inhibits growth in a variety of cancer cell lines; however, its use raises concerns as gut microbiota and the host’s hepatic cytochrome P450 enzymes metabolize it into the most potent phytoestrogen known, 8-prenylnaringenin (8-PN). The XN derivatives dihydroxanthohumol (DXN) and tetrahydroxanthohumol (TXN) are not metabolized into 8-PN and they show higher tissue concentrations in vivo compared with XN when orally administered to mice at the same dose. Here we show that DXN and TXN possess improved anti-proliferative activity compared with XN in two colon (HCT116, HT29) and two hepatocellular (HepG2, Huh7) carcinoma cell lines, as indicated by their respective IC₅₀ values. Furthermore, XN, DXN, and TXN induce extensive apoptosis in all these carcinoma cell lines. Finally, TXN induces G₀/G₁ cell cycle arrest in the colon carcinoma cell line HT29. Our findings suggest that DXN and TXN could show promise as therapeutic agents against colorectal and liver cancer in preclinical studies without the drawback of metabolism into a phytoestrogen. Full article

(This article belongs to the Special Issue Bioactive Phytochemicals for Cancer Prevention and Treatment)

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13 pages, 3099 KiB

Open AccessArticle

Thymoquinone Selectively Kills Hypoxic Renal Cancer Cells by Suppressing HIF-1α-Mediated Glycolysis

by Yoon-Mi Lee, Geon-Hee Kim, Eun-Ji Park, Taek-In Oh, Sujin Lee, Sang-Yeon Kan, Hyeji Kang, Byeong Mo Kim, Ji Hyung Kim and Ji-Hong Lim

Int. J. Mol. Sci. 2019, 20(5), 1092; https://doi.org/10.3390/ijms20051092 - 3 Mar 2019

Cited by 33 | Viewed by 4817

Abstract

Several reports have shown that thymoquinone (TQ) effectively attenuates angiogenesis in cancer cells, resulting in suppression of tumor growth. However, it is not yet clear whether TQ reduces hypoxia-inducible factor-1α (HIF-1α) expression in hypoxic cancer cells. Here, we found that TQ was a novel HIF-1α inhibitor through hypoxia response element (HRE)-luciferase assay-based large screening by using 502 natural compounds containing chemical library. TQ reduced HIF-1α protein levels in renal cancer cells; however, it did not affect the HIF-1α protein levels in the presence of proteasome inhibitor, MG132, indicating that the reduction effects of TQ on HIF-1α protein are mediated via the ubiquitination-proteasome dependent pathway. TQ boosted HIF-1α protein degradation, and the mechanism was revealed by inhibiting interaction between HSP90 and HIF-1α. TQ suppressed downstream genes of HIF-1α, indicating negative impact of TQ on HIF-1α transcriptional activities. In addition, TQ altered glucose, lactate, and ATP levels, leading to anaerobic metabolic disturbance. TQ induced apoptosis in hypoxic cancer cells as determined by crystal violet staining and flow cytometry for annexin V-stained cells. Taken together, we suggested that TQ is a potential anticancer agent targeting HIF-1α. Full article

(This article belongs to the Special Issue Bioactive Phytochemicals for Cancer Prevention and Treatment)

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29 pages, 4474 KiB

Open AccessReview

Pharmacological and Therapeutic Applications of Esculetin

by Sourbh Suren Garg, Jeena Gupta, Debasis Sahu and Chuan-Ju Liu

Int. J. Mol. Sci. 2022, 23(20), 12643; https://doi.org/10.3390/ijms232012643 - 20 Oct 2022

Cited by 28 | Viewed by 5366

Abstract

Esculetin is a coumarin compound, which belongs to the class of benzopyrone enriched in various plants such as Sonchus grandifolius, Aesculus turbinata, etc. Free radicals lead to the development of oxidative stress causing inflammation, arthritis, cancer, diabetes, fatty liver disease, etc. These further reduce the efficacy of anticancer drugs, activate inflammatory signaling pathways, degrade joints and cartilage, and disrupt the glycemic index and normal function of liver enzymes. For instance, the current treatment modalities used in arthritis such as non-steroidal anti-inflammatory drugs, disease-modifying anti-rheumatoid drugs, and lipoxygenase inhibitors present limited efficacy and adverse effects. Thus, there is a constant need to find newer and safer alternatives. Esculetin has an immense antioxidative potential thereby alleviating arthritis, diabetes, malignancies, and hepatic disorders. Structurally, esculetin contains two hydroxyl groups, which enhance its ability to function as an antioxidant by inhibiting oxidative stress in pathological conditions. Leukotriene B4 synthesis, NF-κB and MPAK pathway activation, and inflammatory cytokine production are the main causes of bone and joint deterioration in arthritis, whereas esculetin treatment reverses these factors and relieves the disease condition. In contrast, lipid peroxidation caused by upregulation of TGF-β-mediated expression and dysfunction of antioxidant enzymes is inhibited by esculetin therapy, thus reducing liver fibrosis by acting on the PI3K/FoxO1 pathway. Therefore, targeting NF-κB, pro-inflammatory cytokines, TGF-β and oxidative stress may be a therapeutic strategy to alleviate arthritis and liver fibrosis. Full article

(This article belongs to the Special Issue Bioactive Phytochemicals for Cancer Prevention and Treatment)

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24 pages, 3335 KiB

Open AccessReview

Anticancer Activity and Underlying Mechanism of Phytochemicals against Multiple Myeloma

by Beomku Kang, Hyunmin Park and Bonglee Kim

Int. J. Mol. Sci. 2019, 20(9), 2302; https://doi.org/10.3390/ijms20092302 - 9 May 2019

Cited by 15 | Viewed by 4995

Abstract

Multiple myeloma (MM)—a common hematologic malignancy of plasma cells—accounts for substantial mortality and morbidity rates. Due to the advent of novel therapies such as immunomodulatory drugs (IMiDs), proteasome inhibitors (PIs), and monoclonal antibodies (mAbs), response rates were increased and free survival and overall survival have been elevated. However, adverse events including toxicity, neuropathy or continuous relapse are still problems. Thus, development of novel drugs which have less side effects and more effective is needed. This review aims to recapitulate the pharmacologic anti-MM mechanisms of various phytochemicals, elucidating their molecular targets. Keywords related to MM and natural products were searched in PUBMED/MEDLINE. Phytochemicals have been reported to display a variety of anti-MM activities, including apoptosis, cell cycle arrest, antiangiogenesis, and miRNA modulation. Some phytochemicals sensitize the conventional therapies such as dexamethasone. Also, there are clinical trials with phytochemicals such as agaricus, curcumin, and Neovastat regarding MM treatment. Taken together, this review elucidated and categorized the evidences that natural products and their bioactive compounds could be potent drugs in treating MM. Full article

(This article belongs to the Special Issue Bioactive Phytochemicals for Cancer Prevention and Treatment)

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