Pharmacological Utilization of Bergamottin, Derived from Grapefruits, in Cancer Prevention and Therapy

Ko, Jeong-Hyeon,Arfuso, Frank,Sethi, Gautam,Ahn, Kwang Seok MDPI 2018 INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES Vol.19 No.12

<P>Cancer still remains one of the leading causes of death worldwide. In spite of significant advances in treatment options and the advent of novel targeted therapies, there still remains an unmet need for the identification of novel pharmacological agents for cancer therapy. This has led to several studies evaluating the possible application of natural agents found in vegetables, fruits, or plant-derived products that may be useful for cancer treatment. Bergamottin is a furanocoumarin derived from grapefruits and is also a well-known cytochrome P450 inhibitor. Recent studies have demonstrated potent anti-oxidative, anti-inflammatory, and anti-cancer properties of grapefruit furanocoumarin both in vitro and in vivo. The present review focuses on the potential anti-neoplastic effects of bergamottin in different tumor models and briefly describes the molecular targets affected by this agent.</P>

NF-κB in cancer therapy.

Li, Feng,Zhang, Jingwen,Arfuso, Frank,Chinnathambi, Arunachalam,Zayed, M E,Alharbi, Sulaiman Ali,Kumar, Alan Prem,Ahn, Kwang Seok,Sethi, Gautam Springer-Verlag 2015 Archives of toxicology Vol.89 No.5

<P>The transcription factor nuclear factor kappa B (NF-kappa B) has attracted increasing attention in the field of cancer research from last few decades. Aberrant activation of this transcription factor is frequently encountered in a variety of solid tumors and hematological malignancies. NF-kappa B family members and their regulated genes have been linked to malignant transformation, tumor cell proliferation, survival, angiogenesis, invasion/metastasis, and therapeutic resistance. In this review, we highlight the diverse molecular mechanism(s) by which the NF-kappa B pathway is constitutively activated in different types of human cancers, and the potential role of various oncogenic genes regulated by this transcription factor in cancer development and progression. Additionally, various pharmacological approaches employed to target the deregulated NF-kappa B signaling pathway, and their possible therapeutic potential in cancer therapy is also discussed briefly.</P>

Formononetin-induced oxidative stress abrogates the activation of STAT3/5 signaling axis and suppresses the tumor growth in multiple myeloma preclinical model

Kim, Chulwon,Lee, Seok-Geun,Yang, Woong Mo,Arfuso, Frank,Um, Jae-Young,Kumar, Alan Prem,Bian, Jinsong,Sethi, Gautam,Ahn, Kwang Seok Elsevier 2018 Cancer letters Vol.431 No.-

<P><B>Abstract</B></P> <P>Aberrant reactions of signal transducer and transcriptional activator (STAT) are frequently detected in multiple myeloma (MM) cancers and can upregulate the expression of multiple genes related to cell proliferation, survival, metastasis, and angiogenesis. Therefore, agents capable of inhibiting STAT activation can form the basis of novel therapies for MM patients. In the present study, we investigated whether the potential anti-cancer effects of Formononetin (FT), a naturally occurring isoflavone derived from <I>Astragalus membranaceus</I>, <I>Trifolium pratense</I>, <I>Glycyrrhiza glabra</I>, and <I>Pueraria lobata</I>, against MM cell lines and human multiple myeloma xenograft tumors in athymic nu/nu mice model are mediated through the negative regulation of STAT3 and STAT5 pathways. Data from the <I>in vitro</I> studies indicated that FT could significantly inhibit cell viability, and induce apoptosis. Interestingly, FT also suppressed constitutive STAT3 (tyrosine residue 705 and serine residue 727) and STAT5 (tyrosine residue 694/699) activation, which correlated with the suppression of the upstream kinases (JAK1, JAK2, and c-Src) in MM cells, and this effect was found to be mediated <I>via</I> an increased production of reactive oxygen species (ROS) due to GSH/GSSG imbalance. Also, FT abrogated STAT3 and STAT5 DNA binding capacity and nuclear translocation. FT induced cell cycle arrest, downregulated the expression of STAT3-regulated anti-apoptotic, angiogenetic, and proliferative gene products; and this correlated with induction of caspase-3 activation and cleavage of PARP. Intraperitoneal administration of FT significantly suppressed the tumor growth in the multiple myeloma xenograft mouse model without exhibiting any significant adverse effects. Overall, our findings indicate that FT exhibits significant anti-cancer effects in MM that may be primarily mediated through the ROS-regulated inhibition of the STAT3 and STAT5 signaling cascade.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Formononetin (FT) attenuated constitutive STAT3 and STAT5 activation in MM cells <I>via</I> an increased production of reactive oxygen species (ROS) due to GSH/GSSG imbalance. </LI> <LI> FT significantly attenuated the tumor growth in the multiple myeloma xenograft mouse model without exhibiting any significant adverse effects. </LI> <LI> FT treatment also substantially downregulated the expression of STAT3 regulated gene products in tumor tissues obtained from xenograft mouse model. </LI> </UL> </P>

Ascochlorin Enhances the Sensitivity of Doxorubicin Leading to the Reversal of Epithelial-to-Mesenchymal Transition in Hepatocellular Carcinoma

Dai, Xiaoyun,Ahn, Kwang Seok,Wang, Ling Zhi,Kim, Chulwon,Deivasigamni, Amudha,Arfuso, Frank,Um, Jae-Young,Kumar, Alan Prem,Chang, Young-Chae,Kumar, Dhiraj,Kundu, Gopal C.,Magae, Junji,Goh, Boon Cher,H American Association for Cancer Research 2016 Molecular Cancer Therapeutics Vol.15 No.12

<P>Increasing evidence has indicated that epithelial-to-mesenchymal transition (EMT) at the advanced stage of liver cancer not only has the ability to self-renew and progress cancer, but also enables greater resistance to conventional chemo-and radiotherapies. Here, we report that ascochlorin (ASC), an isoprenoid antibiotic, could potentiate the cytotoxic effect of doxorubicin on HCCLM3, SNU387, SNU49, and SK-Hep-1 hepatocellular carcinoma cells, which had a predominantly mesenchymal signature with low expression of E-cadherin but high expression of N-cadherin. Co-administration of ASC reduced doxorubicin-induced invasion/migration and modulated EMT characteristics in mesenchymal cells. This process was probably mediated by the E-cadherin repressors Snail and Slug. In addition, ASC increased sensitivity to doxorubicin treatment by directly inhibiting STAT3 binding to the Snail promoter. We also observed that ASC significantly enhanced the effect of doxorubicin against tumor growth and inhibited metastasis in an HCCLM3_Luc orthotopic mouse model. Collectively, our data demonstrate that ASC can increase sensitivity to doxorubicin therapy and reverse the EMT phenotype via the downregulation of STAT3-Snail expression, which could form the basis of a novel therapeutic approach against hepatocellular carcinoma. (C) 2016 AACR.</P>

The Role of Resveratrol in Cancer Therapy

Ko, Jeong-Hyeon,Sethi, Gautam,Um, Jae-Young,Shanmugam, Muthu K,Arfuso, Frank,Kumar, Alan Prem,Bishayee, Anupam,Ahn, Kwang Seok MDPI 2017 INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES Vol.18 No.12

<P>Natural product compounds have recently attracted significant attention from the scientific community for their potent effects against inflammation-driven diseases, including cancer. A significant amount of research, including preclinical, clinical, and epidemiological studies, has indicated that dietary consumption of polyphenols, found at high levels in cereals, pulses, vegetables, and fruits, may prevent the evolution of an array of diseases, including cancer. Cancer development is a carefully orchestrated progression where normal cells acquires mutations in their genetic makeup, which cause the cells to continuously grow, colonize, and metastasize to other organs such as the liver, lungs, colon, and brain. Compounds that modulate these oncogenic processes can be considered as potential anti-cancer agents that may ultimately make it to clinical application. Resveratrol, a natural stilbene and a non-flavonoid polyphenol, is a phytoestrogen that possesses anti-oxidant, anti-inflammatory, cardioprotective, and anti-cancer properties. It has been reported that resveratrol can reverse multidrug resistance in cancer cells, and, when used in combination with clinically used drugs, it can sensitize cancer cells to standard chemotherapeutic agents. Several novel analogs of resveratrol have been developed with improved anti-cancer activity, bioavailability, and pharmacokinetic profile. The current focus of this review is resveratrol’s in vivo and in vitro effects in a variety of cancers, and intracellular molecular targets modulated by this polyphenol. This is also accompanied by a comprehensive update of the various clinical trials that have demonstrated it to be a promising therapeutic and chemopreventive agent.</P>

Nimbolide-Induced Oxidative Stress Abrogates STAT3 Signaling Cascade and Inhibits Tumor Growth in Transgenic Adenocarcinoma of Mouse Prostate Model

Zhang, Jingwen,Ahn, Kwang Seok,Kim, Chulwon,Shanmugam, Muthu K.,Siveen, Kodappully Sivaraman,Arfuso, Frank,Samym, Ramar Perumal,Deivasigamanim, Amudha,Lim, Lina Hsiu Kim,Wang, Lingzhi,Goh, Boon Cher,K Mary Ann Liebert 2016 ANTIOXIDANTS AND REDOX SIGNALING Vol.24 No.11