Abstract
Purpose: Lovastatin commonly used as a cholesterol-lowering agent due to its inhibitory action on HMG-CoA reductase enzyme. Lovastatin and other statins may reduce the development of melanomas. Our recent research showed that lovastatin can also be used as anticancer agent and especially naturally synthesized lovastatin has more effect on cancer inhibition over the chemically synthesized. Procedure: The present study was designed to test the anticancer activity of naturally extracted lovastatin against Dalton’s Ascites Lymphoma (DAL) cells. Molecular docking of Bax-Bcl-2 and caspase-3 proteins were interacted with lovastatin and 5-Fluorouracil (5-FU) ligands, followed by which different groups of animals were infected with DAL cells and treated with natural and standard lovastatin which are then compared with control groups. Live and dead cells were differentiated by acridine orange/ethidium bromide dual staining, and DNA damage and organ toxicity were assessed through histopathology study. Finally, the expression level of apoptotic protein was done with Bcl-2, Bax, caspase-3 through immunoblot analysis. Results: The entire computational analysis provided the supportive evidence to confirm the natural lovastatin (NL) performing as an anticancer agent and agreed with the experimental results. Interestingly, the caspase-3 has best interaction with natural lovastatin when compared to standard anticancer drug 5-FU. Similarly, the Bax-Bcl-2 protein also has highest interaction with NL than the 5-FU. The cell viability was assessed using trypan blue staining, and the result revealed that the half of inhibitory concentration (IC50) as 150 ppm, which was used as treatment dose for in vivo study. Upon the treatment, the decline of cancer by reduction of body weight, ascites fluid volume, and lengthening of life span were observed. The AO/EB staining clearly showed number of late apoptotic cells in NL and standard lovastatin treated groups, when compared with standard cancer drug (5-FU)-treated group. DNA damage showed clearly high level of DNA damage in animals treated with NL, natural lovastatin, which is evident for the progression of apoptosis. Further, the expression of apoptotic marker protein such as Bcl-2, Bax, and caspase-3 proved that the cancer cells upon treatment undergo cell death through apoptosis. The histopathology of treated and control groups showed that there is no adverse effect on vital organs like liver and kidney. Conclusion: Overall, the present study clearly showed the effective tumor-controlling property of naturally derived lovastatin. However, the detailed molecular investigation would be required to understand the molecular mechanism of action.
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References
Endo A (2010) A historical perspective on the discovery of statins. Proc Jpn Acad Ser B Phys Biol Sci 86:484–493
Outhoff K (2014) Statins: evidence for effectiveness. S Afr Fam Pract 56:5–8
Folkers K, Langsjoen P, Willis R et al (1990) Lovastatin decreases coenzyme Q levels in humans. Proc Natl Acad Sci (USA) 87:8931–8934
Alberts A, Chen J, Kuron G et al (1980) Mevinolin: a highly potent competitive inhibitor of hydroxymethylglutaryl-coenzyme A reductase and a cholesterol-lowering agent. Proc Natl Acad Sci (USA) 77:3957–3961
Tobert JA (2003) Lovastatin and beyond: the history of the HMG-CoA reductase inhibitors. Nat Rev Drug Discov 2:517–526
Gerson RJ, Macdonald JS, Alberts AW et al (1989) Animal safety and toxicology of simvastatin and related hydroxy-methylglutaryl-coenzyme A reductase inhibitors. Am J Med 87:S28–S38
Endo A, Kuroda M, Tsujita Y (1976) ML-236A, ML-236B, and ML-236C, new inhibitors of cholesterogenesis produced by Penicillium citrinum. J Antibiot 29:1346–1348
Keyomarsi K, Sandoval L, Band V, Pardee AB (1991) Synchronization of tumor and normal cells from G1 to multiple cell cycles by lovastatin. Cancer Res 51:3602–3609
Pon D, Abe A, Gupta EK (2015) A review of statin use and prostate cancer. Curr Atheroscler Rep 17:474
Janani B, Saibaba G, Archunan G, Vidhya K, Karunyadevi J, Angayarkanni J (2017) Purification and cytotoxicity study of lovastatin from soil fungi. Asian J Pharm Clin Res 10:258-262
Tian W, Chen C, Lei X, Zhao J, Liang J (2018) CASTp 3.0: computed atlas of surface topography of proteins. Nucleic Acids Res 46:W363-W367
Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254
Laemmli UK (1970) Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 227:680–685
Mittl PR, Di Marco S, Krebs JF et al (1997) Structure of recombinant human CPP32 in complex with the tetrapeptide acetyl-Asp-Val-Ala-Asp fluoromethyl ketone. J Biol Chem 272:6539–6547
Murakami R, Chen C, Lyu S-Y et al (2016) Lovastatin lowers the risk of breast cancer: a population-based study using logistic regression with a random effects model. SpringerPlus 5:1932
Yagi K (1987) Lipid peroxides and human diseases. Chem Phys Lipids 45:337–351
Price VE, Greenfield RE (1958) Anemia in cancer. Adv Cancer Res 5:199–290
Hoagland HC (1982) Hematologic complications of cancer chemotherapy [abstract]. Seminor Oncol 9:95–102P
Fenninger LD, Mider GB (1954) Energy and nitrogen metabolism in cancer. Adv Cancer Res 2:229–253
Noaman E, El-Kabany H (2002) Effect of novel copper compound (Cu-BISDO) and γ-irradiation on copper and zinc concentration, ceruloplasmin and superoxide dismutase activity, in mice loaded with Ehrlich tumor. Egypt J Biomed Sci 9:209–223
El-Din NKB (2004) Protective role of sanumgerman against γ-irradiation–induced oxidative stress in Ehrlich carcinoma-bearing mice. Nutr Res 24:271–291
Gupta M, Mazumder UK, Kumar RS, Kumar TS (2004) Antitumor activity and antioxidant role of Bauhinia racemosa against Ehrlich ascites carcinoma in Swiss albino mice [corrected]. Acta Pharmacol Sin 25:1070–1076
El-Sayyad HI, Ismail MF, Shalaby F et al (2009) Histopathological effects of cisplatin, doxorubicin and 5-flurouracil (5-FU) on the liver of male albino rats. Int J Biol Sci 5:466
Harris SL, Levine AJ (2005) The p53 pathway: positive and negative feedback loops. Oncogene 24:2899–2908
Yu J, Zhang L (2005) The transcriptional targets of p53 in apoptosis control. Biochem Biophys Res Commun 331:851–858
Puls LE, Powell DE, DePriest PD et al (1992) Transition from benign to malignant epithelium in mucinous and serous ovarian cystadenocarcinoma. Gynecol Oncol 47:53–57
Enari M, Sakahira H, Yokoyama H, Okawa K, Iwamatsu A, Nagata S (1998) A caspase-activated DNase that degrades DNA during apoptosis, and its inhibitor ICAD. Nature 391:43–50
Elmore S (2007) Apoptosis: a review of programmed cell death. Toxicol Pathol 35:495–516
Acknowledgements
This work was supported by Department of Science and Technology (DST), Government of India (SR/SO/HS-0131/2008). GA acknowledges the University Grant Commission, New Delhi, for the award of UGC-BSR Faculty Fellow. The facility availed from UGC-SAP phase II and DST-FIST is gratefully acknowledged.
Conflict of interest: The authors have no competing interests to declare.
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Saibaba, G. et al. (2019). Natural Lovastatin (NL) as an Anticancer Agent: Docking and Experimental Studies. In: Gulyás, B., Padmanabhan, P., Fred, A., Kumar, T., Kumar, S. (eds) ICTMI 2017. Springer, Singapore. https://doi.org/10.1007/978-981-13-1477-3_10
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