Abstract
In recent years, microbial cholesterol oxidases have gained great attention due to its widespread use in medical applications for serum cholesterol determination. Streptomyces aegyptia strain NEAE-102 exhibited high level of extracellular cholesterol oxidase production using a minimum medium containing cholesterol as the sole source of carbon. Fifteen variables were screened using Plackett–Burman design for the enhanced cholesterol oxidase production. The most significant variables affecting enzyme production were further optimized by using the face-centered central composite design. The statistical optimization resulted in an overall 4.97-fold increase (15.631 UmL−1) in cholesterol oxidase production in the optimized medium as compared with the unoptimized medium before applying Plackett Burman design (3.1 UmL−1). The purified cholesterol oxidase was evaluated for its in vitro anticancer activities against five human cancer cell lines. The selectivity index values on rhabdomyosarcoma and breast cancer cell lines were 3.26 and 2.56; respectively. The in vivo anticancer activity of cholesterol oxidase was evaluated against Ehrlich solid tumor model. Compared with control mice, tumors growth was significantly inhibited in the mice injected with cholesterol oxidase alone, doxorubicin alone and cholesterol oxidase/doxorubicin combination by 60.97%, 72.99% and 97.04%; respectively. These results demonstrated that cholesterol oxidase can be used as a promising natural anticancer drug.
Highlights
Cardiovascular diseases are related to high blood cholesterol level and colon cancer has been hypothesized to be associated with its degradation products[1]
This study aimed to optimize the cultural conditions for a higher production of cholesterol oxidase by Streptomyces aegyptia NEAE-102 including the screening of the variables influencing cholesterol oxidase production using Plackett-Burman design, determination of the optimum levels of the significant factors that influence the production of cholesterol oxidase using face-centered central composite design and to assess the in vitro anticancer activities of cholesterol oxidase treatment on various human cancer cell lines
The present study involved the use of statistical experimental designs to optimize nutritional and environmental variables for production of cholesterol oxidase from Streptomyces aegyptia strain NEAE-102
Summary
Cardiovascular diseases are related to high blood cholesterol level and colon cancer has been hypothesized to be associated with its degradation products (cholesterol oxides)[1]. Cholesterol oxidase displays a broad range of clinical applications in laboratories such as cholesterol levels quantification in foods and serum which is important in the diagnosis of atherosclerosis, cardiovascular disease and other lipid disorders[5,6]. When used in lung cancer treatment “both in vitro and in vivo led to irreversible cell apoptosis by reducing cholesterol content and rising reactive oxygen species level. For this reason, cholesterol oxidase may be a promising enzyme for a novel anti-tumor therapy” as reported by Liu et al.[13]. Many microorganisms were demonstrated to produce cholesterol oxidase including Mycobacterium species and Nocardia rhodochrous[14] which produce cholesterol oxidases as an intrinsic membrane bound enzymes located on the outside of the cell, whereas Streptomyces fradiae[15], Streptomyces violascens, Streptomyces parvus[16], Streptoverticilium cholesterolicum[17], Rhodococcus erythropolis and Rhodococcus equi, Arthrobacter simplex and Shizophylum commune[18] produce extracellular cholesterol oxidase in the broth filtrate
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