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      Antineoplastic and Apoptotic Potential of Traditional Medicines Thymoquinone and Diosgenin in Squamous Cell Carcinoma

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          Abstract

          Thymoquinone (TQ) and diosgenin (DG), the active ingredients obtained from black cumin ( Nigella sativa) and fenugreek ( Trigonella foenum graecum), respectively, exert potent bioactivity, including anticancer effects. This study investigated the antineoplastic activity of these agents against squamous cell carcinoma in vitro and sarcoma 180–induced tumors in vivo. TQ and DG inhibited cell proliferation and induced cytotoxicity in A431 and Hep2 cells. These agents induced apoptosis by increasing the sub-G 1 population, LIVE/DEAD cytotoxicity, chromatin condensation, DNA laddering and TUNEL-positive cells significantly ( P<0.05). Increased Bax/Bcl-2 ratio, activation of caspases and cleavage of poly ADP ribose polymerase were observed in treated cells. These drugs inhibited Akt and JNK phosphorylations, thus inhibiting cell proliferation while inducing apoptosis. In combination, TQ and DG had synergistic effects, resulting in cell viability as low as 10%. In a mouse xenograft model, a combination of TQ and DG significantly ( P<0.05) reduced tumor volume, mass and increased apoptosis. TQ and DG, alone and in combination, inhibit cell proliferation and induce apoptosis in squamous cell carcinoma. The combination of TQ and DG is a potential antineoplastic therapy in this common skin cancer.

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          Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors.

          P Talalay, T C Chou (1984)
          A generalized method for analyzing the effects of multiple drugs and for determining summation, synergism and antagonism has been proposed. The derived, generalized equations are based on kinetic principles. The method is relatively simple and is not limited by whether the dose-effect relationships are hyperbolic or sigmoidal, whether the effects of the drugs are mutually exclusive or nonexclusive, whether the ligand interactions are competitive, noncompetitive or uncompetitive, whether the drugs are agonists or antagonists, or the number of drugs involved. The equations for the two most widely used methods for analyzing synergism, antagonism and summation of effects of multiple drugs, the isobologram and fractional product concepts, have been derived and been shown to have limitations in their applications. These two methods cannot be used indiscriminately. The equations underlying these two methods can be derived from a more generalized equation previously developed by us (59). It can be shown that the isobologram is valid only for drugs whose effects are mutually exclusive, whereas the fractional product method is valid only for mutually nonexclusive drugs which have hyperbolic dose-effect curves. Furthermore, in the isobol method, it is laborious to find proper combinations of drugs that would produce an iso-effective curve, and the fractional product method tends to give indication of synergism, since it underestimates the summation of the effect of mutually nonexclusive drugs that have sigmoidal dose-effect curves. The method described herein is devoid of these deficiencies and limitations. The simplified experimental design proposed for multiple drug-effect analysis has the following advantages: It provides a simple diagnostic plot (i.e., the median-effect plot) for evaluating the applicability of the data, and provides parameters that can be directly used to obtain a general equation for the dose-effect relation; the analysis which involves logarithmic conversion and linear regression can be readily carried out with a simple programmable electronic calculator and does not require special graph paper or tables; and the simplicity of the equation allows flexibility of application and the use of a minimum number of data points. This method has been used to analyze experimental data obtained from enzymatic, cellular and animal systems.
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            Targeting nuclear factor-kappa B activation pathway by thymoquinone: role in suppression of antiapoptotic gene products and enhancement of apoptosis.

            Gautam Sethi, Kwang Seok Ahn, Bharat B. Aggarwal (2008)
            Thymoquinone (TQ), derived from the medicinal plant Nigella sativa, exhibits antiinflammatory and anticancer activities through mechanism(s) that is not fully understood. Because numerous effects modulated by TQ can be linked to interference with the nuclear factor-kappaB (NF-kappa B) signaling, we investigated in detail the effect of this quinone on NF-kappa B pathway. As examined by DNA binding, we found that TQ suppressed tumor necrosis factor-induced NF-kappa B activation in a dose- and time-dependent manner and inhibited NF-kappaB activation induced by various carcinogens and inflammatory stimuli. The suppression of NF-kappaB activation correlated with sequential inhibition of the activation of I kappa B alpha kinase, I kappa B alpha phosphorylation, I kappa B alpha degradation, p65 phosphorylation, p65 nuclear translocation, and the NF-kappa B-dependent reporter gene expression. TQ specifically suppressed the direct binding of nuclear p65 and recombinant p65 to the DNA, and this binding was reversed by DTT. However, TQ did not inhibit p65 binding to DNA when cells were transfected with the p65 plasmid containing cysteine residue 38 mutated to serine. TQ also down-regulated the expression of NF-kappa B-regulated antiapoptotic (IAP1, IAP2, XIAP Bcl-2, Bcl-xL, and survivin), proliferative (cyclin D1, cyclooxygenase-2, and c-Myc), and angiogenic (matrix metalloproteinase-9 and vascular endothelial growth factor) gene products. This led to potentiation of apoptosis induced by tumor necrosis factor and chemotherapeutic agents. Overall, our results indicate that the anticancer and antiinflammatory activities previously assigned to TQ may be mediated in part through the suppression of the NF-kappa B activation pathway, as shown here, and thus may have potential in treatment of myeloid leukemia and other cancers.
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              Thymoquinone is a potent superoxide anion scavenger.

              Osama A Badary, Sasha H Wahab, Mohamed Mahdy … (2003)
              The antioxidant and pro-oxidant effects of thymoquinone (TQ), a natural main constituent of the volatile oil of Nigella saliva seeds, and a synthetic structurally-related tert-butylhydroquinone (TBHQ), were examined in vitro. Both TQ and TBHQ efficiently inhibited iron-dependent microsomal lipid peroxidation in a concentration-dependent manner with median inhibitory concentration (IC50) values of 16.8 and 14.9 microM, respectively. TBHQ was stronger than TQ as a scavenger of 2,2'-diphenyl-p-picrylhydrazyl radical (DPPH) (IC50 = 5 microM, 200 times more active than TQ) and as a scavenger of hydroxyl radical (OH*) with an IC50 of 4.6 microM (approximately 10 times more active than TQ). TQ was more active than TBHQ as a superoxide anion scavenger with IC50 of 3.35 microM compared to 18.1 microM for TBHQ. Only TBHQ significantly promoted DNA damage in the bleomycin-Fe(III) system. The results suggest that both TQ and TBHQ have strong antioxidant potentials through scavenging ability of different free radicals. Moreover, the data indicate that TQ is acting mainly as a potent superoxide anion scavenger.
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                Author and article information

                Contributors
                Demetrios Vavvas: Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (iso-abbrev): PLoS ONE
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, USA )
                ISSN (Electronic): 1932-6203
                Publication date Collection: 2012
                Publication date (Electronic): 15 October 2012
                Volume: 7
                Issue: 10
                Electronic Location Identifier: e46641
                Affiliations
                [1 ]School of Medical Science and Technology, Indian Institute of Technology-Kharagpur, West Bengal, India
                [2 ]Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
                [3 ]Department of Human Physiology with Community Health, Vidyasagar University, West Midnapur, West Bengal, India
                [4 ]Department of Biotechnology, Indian Institute of Technology-Kharagpur, West Bengal, India
                Massachusetts Eye & Ear Infirmary, Harvard Medical School, United States of America
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: MM SD. Performed the experiments: SD KKD GD. Analyzed the data: MM SD SM. Contributed reagents/materials/analysis tools: SD IP AM. Wrote the paper: SD MM SCK AM.

                Article
                Publisher ID: PONE-D-12-11354
                DOI: 10.1371/journal.pone.0046641
                PMC ID: 3471895
                PubMed ID: 23077516
                SO-VID: 00c0a57a-7773-4170-8c67-a7afb2e8a097
                Copyright statement: Copyright @ 2012
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Date received : 19 April 2012
                Date accepted : 3 September 2012
                Page count
                Pages: 12
                Funding
                The authors are very thankful to the Department of Science and Technolgy, and the Department of Biotechnology, Government of India for financial support. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Subject: Research Article
                Subject: Biology
                Subject: Histology
                Subject: Immunology
                Subject: Immunopathology
                Subject: Molecular Cell Biology
                Subject: Signal Transduction
                Subject: Signaling Cascades
                Subject: Akt Signaling Cascade
                Subject: c-Jun N-terminal kinase signaling cascade
                Subject: Cell Death
                Subject: Cell Growth
                Subject: Cellular Stress Responses
                Subject: Cellular Structures
                Subject: Medicine
                Subject: Dermatology
                Subject: Skin Neoplasms
                Subject: Malignant Skin Neoplasms
                Subject: Squamous Cell Carcinomas
                Subject: Non-Clinical Medicine
                Subject: Oncology
                Subject: Cancers and Neoplasms
                Subject: Skin Tumors
                Subject: Squamous Cell Carcinoma

                ScienceOpen disciplines: Uncategorized
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                ScienceOpen disciplines: Uncategorized

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