Abstract
The hepatoprotective activity of heliomycin obtained from the culture broth of actinomycete AB5 against diethylnitrosamine (DEN)-induced hepatic cancer in Wistar rats was estimated. Heliomycin exhibited a significant decrease in the levels of alanine transaminase (ALT), aspartate transaminase (AST), and alkaline phosphatase (ALP) compared to the positive control. For instance, the heliomycin group after 20 weeks showed a significant decline in ALT, AST, and ALP values (70.75 ± 5.12, 140.25 ± 11.75, and 163.25 ± 18.66, respectively) compared to the positive control group (170.00 ± 9.55, 252.75 ± 12.33, and 278.00 ± 21.32, respectively). Additionally, the isolated compound showed a highly significant decrease in serum alpha-fetoprotein (AFP) levels. After 8, 16, and 20 weeks, the mean values of AFP in the heliomycin group revealed a highly significant decrease (33.62 ± 2.46, 30.00 ± 4.05, and 28.50 ± 2.64, respectively) compared to the positive control group (49.45 ± 3.03, 81.90 ± 6.70, and 90.75 ± 5.12, respectively). The histopathological investigation of liver sections supported the results of biochemical analysis. It was demonstrated that heliomycin showed histological improvement of hepatocytes and marked increase of nuclear pyknotic with clear cytoplasm, which is a sign of improving the apoptotic pathway of malignant cells. It also displayed marked fibrosis at most of the malignant cells and the development of some regenerative nodules. Heliomycin showed moderate immunoreactivity with alpha-fetoprotein (AFP), and proliferation cell nuclear antigen (PCNA) compared to the positive control group. To the best of our knowledge, this is the first study to report the anticancer activity of heliomycin against hepatocellular carcinoma in vivo.
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References
Abdelfattah MS, Rohr J (2006) Premithramycinone G, an early shunt product of the mithramycin biosynthetic pathway accumulated upon inactivation of oxygenase MtmOII. Angew Chem Int Ed 45:5685–5689. https://doi.org/10.1002/anie.200600511
Abdelfattah MS, Toume K, Ishibashi M (2011) Izumiphenazine D, a new phenazoquinoline N-oxide from Streptomyces sp. IFM 11204. Chem Pharm Bull. https://doi.org/10.1248/cpb.59.508
Abdelfattah MS, Arai MA, Ishibashi M (2016a) Bioactive secondary metabolites with unique aromatic and heterocyclic structures obtained from terrestrial actinomycetes species. Chem Pharm Bull 64:668–675. https://doi.org/10.1248/cpb.c16-00038
Abdelfattah MS, Elmallah MIY, Hawas UW, Abou el-Kassema LT, Eid MAG (2016b) Isolation and characterization of marine-derived actinomycetes with cytotoxic activity from the Red Sea coast. Asian Pac J Trop Biomed 6:651–657. https://doi.org/10.1016/j.apjtb.2016.06.004
Abdelfattah MS, Elmallah MIY, Faraag AHI et al (2018) Heliomycin and tetracinomycin D: anthraquinone derivatives with histone deacetylase inhibitory activity from marine sponge-associated Streptomyces sp. SP9. 3 Biotech. https://doi.org/10.1007/s13205-018-1304-1
Adinarayana G, Venkateshan MR, Bapiraju VVSNK, Sujatha P, Premkumar J, Ellaiah P, Zeeck A (2006) Cytotoxic compounds from the marine actinobacterium Streptomyces corchorusii AUBN1/71. Russ J Bioorg Chem 32:295–300. https://doi.org/10.1134/S1068162006030125
Alturkistani HA, Tashkandi FM, Mohammedsaleh ZM (2015) Histological stains: a literature review and case study. Global J Health Sci 8:72–79. https://doi.org/10.5539/gjhs.v8n3p72
Ashtari S, Pourhoseingholi MA, Sharifian A, Zali MR (2015) Hepatocellular carcinoma in Asia: prevention strategy and planning. World J Hepatol 7:1708–1717
Badr SEA, Abdelfattah MS, El-Sayed SH et al (2014) Evaluation of anticancer, antimycoplasmal activities and chemical composition of guar (Cyamopsis tetragonoloba) seeds extract. Res J Pharm, Biol Chem Sci 5:413–423
Barka EA, Vatsa P, Sanchez L, Gaveau-Vaillant N, Jacquard C, Meier-Kolthoff JP, Klenk HP, Clément C, Ouhdouch Y, van Wezel G (2016) Taxonomy, physiology, and natural products of actinobacteria. Microbiol Mol Biol Rev 80:1–43. https://doi.org/10.1128/mmbr.00019-15
Bergmeyer HU, Hørder M, Rej R (1986a) International Federation of Clinical Chemistry (IFCC) Scientific Committee, Analytical Section: approved recommendation (1985) on IFCC methods for the measurement of catalytic concentration of enzymes. Part 3. IFCC method for alanine aminotransferase (L-a). J Clin Chem Clin Biochem 24:481–495
Bergmeyer HU, Hørder M, Rej R (1986b) International Federation of Clinical Chemistry (IFCC) Scientific Committee, Analytical Section: approved recommendation (1985) on IFCC methods for the measurement of catalytic concentration of enzymes. Part 2. IFCC method for aspartate aminotransferase (L). J Clin Chem Clin Biochem 24:497–510
Blunt JW, Copp BR, Keyzers RA, Munro MHG, Prinsep MR (2012) Marine natural products. Nat Prod Rep 29:144–222. https://doi.org/10.1039/c2np00090c
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A (2018) Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 68:394–424. https://doi.org/10.3322/caac.21492
Brockmann H, Schmidt-Kastner G (1951) Resistomycin, ein neues Antibioticum aus Actinomyceten. Naturwissenschaften 38:479–480. https://doi.org/10.1007/BF00622090
Bruce RD (1985) An up-and-down procedure for acute toxicity testing. Fundam Appl Toxicol 5:151–157
Chakraborty T, Chatterjee A, Rana A, Dhachinamoorthi D, Kumar P A, Chatterjee M (2007) Carcinogen-induced early molecular events and its implication in the initiation of chemical hepatocarcinogenesis in rats: chemopreventive role of vanadium on this process. Biochim Biophys Acta Mol basis Dis 1772:48–59. https://doi.org/10.1016/J.BBADIS.2006.10.019
Chen S, Flower A, Ritchie A, Liu J, Molassiotis A, Yu H, Lewith G (2010) Oral Chinese herbal medicine (CHM) as an adjuvant treatment during chemotherapy for non-small cell lung cancer: a systematic review. Lung Cancer 68:137–145. https://doi.org/10.1016/j.lungcan.2009.11.008
Citron CA, Rabe P, Dickschat JS (2012) The scent of bacteria: headspace analysis for the discovery of natural products. J Nat Prod 75:1765–1776. https://doi.org/10.1021/np300468h
Dai Z-J, Wu W-Y, Kang H-F, Ma XB, Zhang SQ, Min WL, Kang WF, Ma XB, Zhang SQ, Min WL, Lu WF, Lin S, Wang XJ (2013) Protective effects of Scutellaria barbata against rat liver tumorigenesis. Asian Pac J Cancer Prev 14:261–265. https://doi.org/10.7314/apjcp.2013.14.1.261
Darwish HA, El-Boghdady NA (2013) Possible involvement of oxidative stress in diethylnitrosamine-induced hepatocarcinogenesis: chemopreventive effect of curcumin. J Food Biochem 37:353–361. https://doi.org/10.1111/j.1745-4514.2011.00637.x
De Minicis S, Kisseleva T, Francis H et al (2013) Liver carcinogenesis: rodent models of hepatocarcinoma and cholangiocarcinoma. Dig Liver Dis 45:450–459. https://doi.org/10.1016/j.dld.2012.10.008
Dias DA, Urban S, Roessner U (2012) A historical overview of natural products in drug discovery. Metabolites 2:303–336
Elmallah MIY, Micheau O, Eid MAG, Hebishy AMS, Abdelfattah MS (2017) Marine actinomycete crude extracts with potent TRAIL-resistance overcoming activity against breast cancer cells. Oncol Rep 37:3635–3642. https://doi.org/10.3892/or.2017.5595
Elmallah MIY, Cogo S, Constantinescu AA, Elifio-Esposito S, Abdelfattah MS, Micheau O (2020) Marine actinomycetes-derived secondary metabolites overcome TRAIL-resistance via the intrinsic pathway through downregulation of survivin and XIAP. Cells 9:1760. https://doi.org/10.3390/cells9081760
Ghouri YA, Mian I, Rowe JH (2017) Review of hepatocellular carcinoma: epidemiology, etiology, and carcinogenesis. J Carcinog 16:1–8
Gnanaraja R, Prakash V (2014) Preventive effect of tephrosia purpurea against N,N-diethylnitrosamine induced hepatocellular carcinoma in Swiss Albino mice. J Biol Life Sci 5:1. https://doi.org/10.5296/jbls.v5i2.5276
Guicciardi ME, Gores GJ (2009) Life and death by death receptors. FASEB J 23:1625–1637. https://doi.org/10.1096/fj.08-111005
Haupt I, Wähnert U, Pitra C, Löber G, Luck G, Eckardt K (1975) Effects of the antibiotic resistomycin on the synthesis of macromolecules. Z Allg Mikrobiol 15:411–421. https://doi.org/10.1002/jobm.19750150604
Hayashi T, Yamashita T, Okada H et al (2017) A novel mTOR inhibitor; anthracimycin for the treatment of human hepatocellular carcinoma. Anticancer Res 37:3397–3403. https://doi.org/10.21873/anticanres.11706
Jahan MS, Vani G, Shyamalade CS (2011) Anti-carcinogenic effect of Solanum trilobatum in diethylnitrosamine induced and phenobarbital promoted heaptocarcinogenesis in rats. Asian J Biochem 6:74–81. https://doi.org/10.3923/ajb.2011.74.81
Karpiński T, Adamczak A (2018) Anticancer activity of bacterial proteins and peptides. Pharmaceutics 10:54. https://doi.org/10.3390/pharmaceutics10020054
Ko JK, Auyeung KK (2012) Target-oriented mechanisms of novel herbal therapeutics in the chemotherapy of gastrointestinal cancer and inflammation. Curr Pharm Des 19:48–66. https://doi.org/10.2174/13816128130109
Kock I, Maskey RP, Biabani MAF, Helmke E, Laatsch H (2005) 1-Hydroxy-1-norresistomycin and resistoflavin methyl ether: new antibiotics from marine-derived Streptomycetes†, ††. J Antibiot (Tokyo) 58:530–534. https://doi.org/10.1038/ja.2005.73
Kohli A (2016) The relationship between hepatocellular carcinoma and hepatitis B and C virus. Gastroenterol Hepatol (N Y) 12:116–118
Kumar VR, Gouda TS, Sreelakshmi S, Rajasekar R, Munawar MS (2014) Protective potential of hesperidin against diethylnitrosamine induced hepatocarcinogenesis in rats. J Drug Discov Ther 2:12–16
Liu J-G, Zhao H-J, Liu Y-J, Liu YW, Wang XL (2012) Effect of two selenium sources on hepatocarcinogenesis and several angiogenic cytokines in diethylnitrosamine-induced hepatocarcinoma rats. J Trace Elem Med Biol 26:255–261. https://doi.org/10.1016/j.jtemb.2012.02.001
Mahmoud AA, Essawy EA, Abdalla MS, Abdelfattah MS (2019) Production of heliomycin from actinomycete and evaluation of its antimicrobial activities. J Biosci Appl Res 5(4):429–436
Nyblom H, Berggren U, Balldin J, Olsson R (2004) High ast/alt ratio may indicate advanced alcoholic liver disease rather than heavy drinking. Alcohol Alcohol 39:336–339. https://doi.org/10.1093/alcalc/agh074
Perumal S, Langeshwaran K, Selvaraj J, Ponnulakshmi R, Shyamaladevi B, Balasubramanian MP (2018) Effect of diosmin on apoptotic signaling molecules in N-nitrosodiethylamine-induced hepatocellular carcinoma in experimental rats. Mol Cell Biochem 449:27–37. https://doi.org/10.1007/s11010-018-3339-3
Podol’ skaya SV, Naryshkina NA, Sorokoumova GM et al (2005) Antiviral activity of liposomal preparations of antibiotic geliomycin. Bull Exp Biol Med 139:349–351. https://doi.org/10.1007/s10517-005-0291-5
Raguz S, Yagüe E (2008) Resistance to chemotherapy: new treatments and novel insights into an old problem. Br J Cancer 99:387–391. https://doi.org/10.1038/sj.bjc.6604510
Ramana KV, Singhal SS, Reddy AB (2014) Therapeutic potential of natural pharmacological agents in the treatment of human diseases. Biomed Res Int 2014(573452):4. https://doi.org/10.1155/2014/573452
Rashed WM, Kandeil MAM, Mahmoud MO, Ezzat S (2020) Hepatocellular carcinoma (HCC) in Egypt: a comprehensive overview. J Egypt Natl Canc Inst 32:1–11
Rawla P, Sunkara T, Muralidharan P, Raj JP (2018) Update in global trends and aetiology of hepatocellular carcinoma. Wspolczesna Onkol 22:141–150
Rec G (1972) Optimized standard colorimetric methods. J Clin Chem Clin Biochem 10:182
Schlageter M, Terracciano LM, D’Angelo S, Sorrentino P (2014) Histopathology of hepatocellular carcinoma. World J Gastroenterol 20:15955–15964. https://doi.org/10.3748/wjg.v20.i43.15955
Sell S (2008) Alpha-fetoprotein, stem cells and cancer: how study of the production of alpha-fetoprotein during chemical hepatocarcinogenesis led to reaffirmation of the stem cell theory of cancer. Tumor Biol 29:161–180. https://doi.org/10.1159/000143402
Sell S, Becker F, Leffert H, Osborn K, Salman J, Lombardi B, Shinozuka H, Reddy J, Ruoslahti E, Sala-Trepat J (1983) Alphafetoprotein as a marker for early events and carcinoma development during chemical hepatocarcinogenesis. In: Application of biological markers to carcinogen testing. Springer US, Boston, pp 271–293
Shiono Y, Shiono N, Seo S, Oka S, Yamazaki Y (2002) Effects of polyphenolic anthrone derivatives, resistomycin and hypericin, on apoptosis in human megakaryoblastic leukemia CMK-7 cell line. Z Naturforsch C J Biosci 57:923–929. https://doi.org/10.1515/znc-2002-9-1028
Song Y, Jin S-J, Cui L-H, Ji XJ, Yang FG (2013) Immunomodulatory effect of Stichopus japonicus acid mucopolysaccharide on experimental hepatocellular carcinoma in rats. Molecules 18:7179–7193. https://doi.org/10.3390/molecules18067179
Subramani R, Sipkema D (2019) Marine rare actinomycetes: a promising source of structurally diverse and unique novel natural products. Mar Drugs 17(5):249. https://doi.org/10.3390/md17050249
Takahashi Y, Omura S (2003) Isolation of new actinomycete strains for the screening of new bioactive compounds. J Gen Appl Microbiol 49:141–154
Thavasu PW, Longhurst S, Joel SP, Slevin ML, Balkwill FR (1992) Measuring cytokine levels in blood. Importance of anticoagulants, processing, and storage conditions. J Immunol Methods 153:115–124. https://doi.org/10.1016/0022-1759(92)90313-i
Venturi A, Piaz FD, Giovannini C, Gramantieri L, Chieco P, Bolondi L (2008) Human hepatocellular carcinoma expresses specific PCNA isoforms: an in vivo and in vitro evaluation. Lab Investig 88:995–1007. https://doi.org/10.1038/labinvest.2008.50
Vijayabharathi R, Bruheim P, Andreassen T, Raja DS, Devi PB, Sathyabama S, Priyadarisini VB (2011) Assessment of resistomycin, as an anticancer compound isolated and characterized from Streptomyces aurantiacus AAA5. J Microbiol 49:920–926. https://doi.org/10.1007/s12275-011-1260-5
Wang S-S, Zhang T, Wang X-L, Hong L, Qi QH (2003) Effect of arsenic trioxide on rat hepatocellular carcinoma and its renal cytotoxity. World J Gastroenterol 9:930–935. https://doi.org/10.3748/wjg.v9.i5.930
Wild CP, Gong YY (2009) Mycotoxins and human disease: a largely ignored global health issue. Carcinogenesis 31:71–82
Yang JD, Hainaut P, Gores GJ, Amadou A, Plymoth A, Roberts LR (2019) A global view of hepatocellular carcinoma: trends, risk, prevention and management. Nat Rev Gastroenterol Hepatol 16:589–604
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Conceptualization, M. S. A. and A. S. A.; methodology and data analysis, A. S. A., A. A. M., and M. S. A.; writing the manuscript, M. M. O., A. A. M., and M. S. A.; revised the manuscript, E. A. E. and M. S. A. The authors declare that all data were generated in-house and that no paper mill was used.
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Alazzouni, A.S., Mahmoud, A.A., Omran, M.M. et al. Inhibitory and ameliorative effect of heliomycin derived from actinomycete on induced hepatocellular carcinoma in rats. Naunyn-Schmiedeberg's Arch Pharmacol 394, 1091–1102 (2021). https://doi.org/10.1007/s00210-020-02043-5
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DOI: https://doi.org/10.1007/s00210-020-02043-5