Doxorubicin Supplemented with Pravastatin in Lipid Nanoemulsion Induces Antineoplastic Activity with Limited Hepatotoxicity and Cardiotoxicity in Tumor-Bearing Mice


  • King Abdulaziz University, Regenerative Medicine, Unit King Fahd Center for Medical Research, Jeddah, Saudi Arabia
  • King Abdulaziz University, Department of Pharmacology, Faculty of Medicine, Jeddah, Saudi Arabia
  • King Abdulaziz University, Department of Biochemistry, Faculty of Science, Jeddah, Saudi Arabia
  • King Abdulaziz University, Department of Biology, Faculty of Science, Jeddah, Saudi Arabia
  • Ain Shams University, Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo, 11566, Egypt


Doxorubicin (DXR) is widely indicated as anticancer drug, but serious cardiotoxicity limits its clinical application. Recently, Pravastatin (PS) is one of the statins that appear to possess a potential role in cancer therapy despite its hepatotoxicity. Interestingly, drug delivery systems are designed for targeted and controlled delivery of one or more drugs loaded in nanoparticles, holding an enormous potential in therapeutics. Therefore, the aim of the current study was to assess the tolerability of a novel nanoemulsion formulation holding DXR and pravastatin (DXR+PS/LNE) in Swiss albino mice bearing Ehrlich Ascites Carcinoma (EAC). The efficacy and tolerability of nanoemulsion formulation was assessed by monitoring body weight changes, biochemical and histopathological profiles of cardiac and hepatic tissues. The formulated DXR+PS/ LNE has mean droplet diameter of 139.90±3.85 nm. The present findings indicated that DXR+PS/LNE caused a significant decrease in body weight change and a 217.35 % increase in the mean survival time compared to EAC-challenged mice. In addition, no significant changes in biochemical parameters were detected compared to corresponding controls. The current preclinical results suggest that the nanoemulsion formulation of doxorubicin with pravastatin could be a promising novel cancer therapy, in terms of tolerability.


Cardiac Tissue, Ehrlich Ascites Carcinoma, Hepatic Tissue, Mean Survival Time, Statins, Transmission Electron Microscope

Subject Discipline


Full Text:


Lane RJ, Khin NY, Pavlakis N, Hugh TJ, Clarke SJ, Magnussen J, Rogan C, Flekser RL. Challenges in chemotherapy delivery: comparison of standard chemotherapy delivery to locoregional vascular mass fluid transfer. Future Oncol. 2018; 14(7): 647–663.

Tocchetti CG, Cadeddu C, Di Lisi D, Femminò S, Madonna R, Mele D, Monte I, Novo G, Penna C, Pepe A, Spallarossa P, Varricchi G, Zito C, Pagliaro P, Mercuro G. From molecular mechanisms to clinical management of antineoplastic drug-induced cardiovascular toxicity: A translational overview. Antioxid Redox Signal. 2017; 30(18):2110-2153.

Cai F, Luis M, Lin X, Wang M, Cai L, Cen C, Biskup E. Anthracycline-induced cardiotoxicity in the chemotherapy treatment of breast cancer: Preventive strategies and treatment. Mol Clin Oncol. 2019; 11(1): 15–23.

Alkreathy H, Damanhouri ZA, Ahmed N, Slevin M, Ali SS, Osman AMM. Aged garlic extract protects against doxorubicin-induced cardiotoxicity in rats. Food Chem Toxicol. 2010; 48(3): 951–956.

Sadeghi-Aliabadi H, Minaiyan M, Dabestan A. Cytotoxic evaluation of doxorubicin in combination with simvastatin against human cancer cells. Res Pharm Sci. 2010; 5(2): 127–133.

Zheng J, Lee HCM, bin Sattar MM, Huang Y, Bian JS. Cardioprotective effects of epigallocatechin-3-gallate against doxorubicin-induced cardiomyocyte injury. Eur J Pharmacol. 2011; 652(1–3): 82–88.

Cagel M, Grotz E, Bernabeu E, Moretton MA, Chiappetta DA. Doxorubicin: nanotechnological overviews from bench to bedside. Drug Discov Today. 2017; 22(2): 270– 281.

Alkreathy HM, Alkhatib MH, Al Musaddi SA, Balamash KSA, Osman NN, Ahmad A. Enhanced antiâ€tumor activity of doxorubicin and simvastatin combination loaded nanoemulsion treatment against a Swiss albino mouse model of Ehrlich ascites carcinoma. Clin Exp Pharmacol Physiol. 2019; 46(5): 496–505. https://doi.


Alkreathy HM, Alkhatib MH, Al-thepyani MAH, Balamash KSA, Alghamdi SK, Karim S, Ahmad A. Synergistic antitumor activity of doxorubicin and atorvastatin combination loaded nanoemulsion in mice. Int J Pharmacol. 2020; 16(4): 330–342. ijp.2020.330.342.

Liu S, Li R, Qian J, Sun J, Li J, Shen J, Xie Y. Combination Therapy of Doxorubicin and Quercetin on MultidrugResistant Breast Cancer and Their Sequential Delivery by Reduction-Sensitive Hyaluronic Acid-Based Conjugate/dα-Tocopheryl Poly(ethylene glycol) 1000 Succinate Mixed Micelles. Mol Pharm. 2020; 17(4):1415–1427.

Stroes E. Statins and LDL-cholesterol lowering: an overview. Curr Med Res Opin. 2005; 21 Suppl 6: S9–S16.

Ramkumar S, Raghunath A, Raghunath S. Statin Therapy: Review of Safety and Potential Side Effects. Acta Cardiol Sin. 2016; 32(6): 631–639. ACS20160611A.

Bil J, Zapala L, Nowis D, Jakobisiak M, Golab J. Statins potentiate cytostatic/cytotoxic activity of sorafenib but not sunitinib against tumor cell lines in vitro. Cancer Lett. 2010; 288(1): 57–67.

Zaleska M, Mozenska O, Bil J. Statins use and cancer: an update. Future Oncol. 2018; 14(15): 1497–1509.

Koti BC, Nagathan S, Vishwanathswamy A, Gadad PC, Thippeswamy A. Cardioprotective effect of Vedic Guard against doxorubicin-induced cardiotoxicity in rats: A biochemical, electrocardiographic, and histopathological study. Pharmacogn Mag. 2013; 9(34): 176–181.

Henslee A B, Steele TA. Combination statin and chemotherapy inhibits proliferation and cytotoxicity of an aggressive natural killer cell leukemia. Biomark Res. 2018; 6(1): 26.

Martirosyan A, Clendening JW, Goard CA, Penn LZ. Lovastatin induces apoptosis of ovarian cancer cells and synergizes with doxorubicin: potential therapeutic relevance. BMC Cancer. 2010; 10(1): 103.

Wang A, Wakelee HA, Aragaki AK, Tang JY, Kurian AW, Manson JE, Stefanick ML. Protective effects of statins in cancer: should they be prescribed for high-risk patients? Curr Atheroscler Rep. 2016; 18(12):72.

Cholesterol Treatment Trialists’ (CTT) Collaborators. Efficacy and safety of LDL-lowering therapy among men and women: meta-analysis of individual data from 174 000 participants in 27 randomised trials. Lancet. 2015; 385 (9976): 1397–1405.

Simon MS, Rosenberg CA, Rodabough RJ, Greenland P, Ockene I, Roy HK, Lane DS, Cauley JA, Khandekar J. Prospective analysis of association between use of statins or other lipid-lowering agents and colorectal cancer risk. Ann Epidemiol. 2012; 22(1):17–27.

Murtola TJ, Visvanathan K, Artama M, Vainio H, Pukkala E. Statin use and breast cancer survival: a nationwide cohort study from Finland. PloS One. 2014; 9(10): e110231.

Cardwell CR, Hicks BM, Hughes C, Murray LJ. Statin use after diagnosis of breast cancer and survival: a populationbased cohort study. Epidemiology. 2015; 26(1): 68–78.

Sánchez-López E, Guerra M, Dias-Ferreira J, LopezMachado A, Ettcheto M, Cano A, Espina M, Camins A, Garcia M L, Souto EB. Current Applications of Nanoemulsions in Cancer Therapeutics. Nanomaterials (Basel, Switzerland). 2019; 9(6): 821.

Alkhatib MH, Albishi HM, Mahassni SH. Impact of nanoparticles on cancer therapy. Trop J Pharm Res. 2012; 11(6):1001–1011.

Alkhatib MH, AlBishi HM. In vitro evaluation of antitumor activity of doxorubicin-loaded nanoemulsion in MCF-7 human breast cancer cells. J Nanopart Res. 2013; 15(3): 1489.

Alkreathy HM, Damanhouri ZA, Ahmed N, Slevin M, Osman AMM. Mechanisms of cardioprotective effect of aged garlic extract against doxorubicin-induced cardiotoxicity. Integr Cancer Ther. 2012; 11(4): 364–370.

Raju AB, Ravindranath A, Kalpana G. Antitumor activity of Diospyrosperegrina on Ehrlich ascites carcinoma in mice. J Sci Res. 2011; 3(2): 413–419.

Massing U, Fuxius S. Liposomal formulations of anticancer drugs: selectivity and effectiveness. Drug Resist Updat. 2000; 3(3):171–177.

Karlsson J, Vaughan HJ, Green JJ. Biodegradable Polymeric Nanoparticles for Therapeutic Cancer Treatments. Annu Rev Chem Biomol Eng. 2018; 9: 105–127.

Danaei M, Dehghankhold M, Ataei S, Hasanzadeh Davarani F, Javanmard R, Dokhani A, Khorasani S, Mozafari MR. Impact of particle size and polydispersity index on the clinical applications of lipidic nanocarrier systems. Pharmaceutics. 2018; 10(2): 57.

Rašković A, Stilinović N, Kolarović J, Vasović V, Vukmirović S, Mikov M. The protective effects of silymarin against doxorubicin-induced cardiotoxicity and hepatotoxicity in rats. Molecules. 2011; 16(10):8601–8613.

Zombeck JA, Fey EG, Lyng GD, Sonis ST. A clinically translatable mouse model for chemotherapy-related fatigue. Comp Med. 2013; 63(6): 491–497.

Hijona E, Banales JM, Hijona L, Medina JF, Arenas J, Herreros-Villanueva M, Aldazabal P, Bujanda L. Pravastatin inhibits cell proliferation and increased MAT1A expression in hepatocarcinoma cells and in vivo models. Cancer Cell Int. 2012; 12(1): 5.

Kubitz R, Merker G, Häussinger D. Hepatomegaly. Encyclopedia of Molecular Mechanisms of Disease. 2009; 824–825.

Soliman HA, Ahmed RR, Ali AT. Assessment of the chemopreventive effects of various plant constituents against doxorubicin-induced toxicity in rats. J Am Sci. 2014; 10:153–164.

Salouege I, Ben Ali R, Ben Saïd D, Elkadri N, Kourda N, Lakhal M, Klouz A. Means of evaluation and protection from doxorubicin-induced cardiotoxicity and hepatotoxicity in rats. J Cancer Res Ther. 2014; 10(2): 274–278.

Divakaran SA, Nai CK. Amelioration of doxorubicin induced cardiotoxicity in tumor bearing mice by ferulic acid: a mechanistic study at cellular and biochemical level. Int J Tumor Therap. 2012; 1 (2): 6–13.

Gandhi H, Patel V, Mistry N, Patni N, Nandania J, Balaraman R. Doxorubicin mediated cardiotoxicity in rats: Protective role of felodipine on cardiac indices. Environ Toxicol Pharmacol. 2013; 36: 787–795.

Park J, Fong PM, Lu J, Russell KS, Booth CJ, Saltzman WM, Fahmy TM. PEGylated PLGA nanoparticles for the improved delivery of doxorubicin. Nanomedicine. 2009; 5(4):410–418.

Henninger C, Fritz G. Statins in anthracycline-induced cardiotoxicity: Rac and Rho, and the heartbreakers. Cell Death Dis. 2017; 8(1): e2564–e2564.

Haldar PK, Kar B, Bala A, Bhattacharya S, Mazumder UK. Antitumor activity of Sansevieria roxburghiana rhizome against Ehrlich ascites carcinoma in mice. Pharm Biol. 2010; 48(12): 1337–1343.

Hao H, Ma Q, Huang C, He F, Yao P. Preparation, characterization, and in vivo evaluation of doxorubicin loaded BSA nanoparticles with folic acid modified dextran surface. Int J Pharm. 2013; 444(1–2): 77–84.

Kawata S, Yamasaki E, Nagase T, Inui Y, Ito N, Matsuda Y, Inada M, Tamura S, Noda S, Imai Y, Matsuzawa Y. Effect of pravastatin on survival in patients with advanced hepatocellular carcinoma. A randomized controlled trial. Br J Cancer. 2001; 84(7): 886–891.


  • There are currently no refbacks.