The Encapsulation of Febuxostat into Emulsomes Strongly Enhances the Cytotoxic Potential of the Drug on HCT 116 Colon Cancer Cells.

Usama A Fahmy,Helal H Alsulimani,Hibah M Aldawsari,Osama A A Ahmed,Shaimaa M Badr-Eldin,Nabil A Alhakamy,Giuseppe Caruso,Filippo Caraci

doi:10.3390/pharmaceutics12100956

Abstract

Febuxostat (FBX) is a drug able to inhibit xanthine oxidase and reduce uric acid production commonly used for the treatment of hyperuricemia in subjects suffering from gout. Several studies have also been directed at its use as anti-cancer drug during the last years, opening a window for its off-label use. In the present study, an optimized formulation in terms of vesicle size and drug release, obtained by encapsulation of FBX into the emulsomes (FBX-EMLs), was evaluated for its cytotoxic potential in human colorectal carcinoma (HCT 116) cells. The optimized FBX-EMLs formula had an improved half maximal inhibitory concentration (IC50), about 4-fold lower, compared to the free drug. The cell cycle analysis showed a significant inhibition of the HCT 116 cells proliferation following FBX-EMLs treatment compared to all the other conditions, with a higher number of cells accumulating on G2/M and pre-G1 phases, paralleled by a significant reduction of cells in G0/G1 and S phases. The optimized formula was also able to significantly increase the percentage of cell population in both early and late stages of apoptosis, characterized by a higher intracellular caspase-3 concentration, as well as percentage of necrotic cells. Lastly, the FBX ability to decrease the mitochondrial membrane potential was enhanced when the drug was delivered into the EMLs. In conclusion, the new formulation of FBX into EMLs improved all the parameters related to the anti-proliferative activity and the toxic potential of the drug towards colorectal cancer cells.

Highlights

Cancer is a major health issue, as it involves several molecular mechanisms that cause uncontrolled proliferation due to abnormal cell signaling [1]
Based on the information available on the Global Cancer Observatory (GCO), an interactive web-based platform presenting global cancer statistics to inform cancer control and research, colorectal cancer occupies the second position for number of deaths (∼880 thousand; 9.2%), the third position for estimated number of new cases (∼1.85 million; 10.2%), and the second position with regard to the expected number of prevalent cases (5 years) (∼4.8 million; 10.9%) worldwide (Data source: GLOBOCAN 2018)
We investigated a new possible strategy to treat colorectal cancer by formulating molecules with known pharmacological use in other diseases, minimizing the required preclinical toxicological studies necessary before drug approval [9]

Summary

Introduction

Cancer is a major health issue, as it involves several molecular mechanisms that cause uncontrolled proliferation due to abnormal cell signaling [1]. By year 2040, the mortality rate as well as the incidence of this type of cancer is expected to rise significantly [4] Several risk factors such as obesity, sedentary lifestyle, red meat consumption, androgen deprivation therapy, smoking, and alcohol intake are considered to contribute significantly to colorectal cancer development [5]. This type of cancer is often diagnosed at an advanced stage when the dissemination of tumor cells have already occurred, with a five-year survival prognosis strictly dependent on the stage of the disease (90% survival for patients with stage I vs 10% survival for patients with stage IV) [6]. We investigated a new possible strategy to treat colorectal cancer by formulating molecules with known pharmacological use in other diseases (drug repositioning), minimizing the required preclinical toxicological studies necessary before drug approval [9]

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Discussion

Conclusion