Abstract
Tumour cells maintain a local hypoxic and acidic microenvironment which plays a crucial role in cancer progression and drug resistance. Urease is a metallohydrolases that catalyses the hydrolysis of urea into ammonia and carbon dioxide, causing an abrupt increase of pH. This enzymatic activity can be employed to target the acidic tumour microenvironment. In this study, we present the anticancer activities of urease mimetic cobalt (III) complexes on A549 cells. The cells were treated with different doses of cobalt (III) complexes to observe the cytotoxicity. The change in cellular morphology was observed using an inverted microscope. The cell death induced by these complexes was analysed through ATP proliferation, LDH release and caspase 3/7 activity. The effect of extracellular alkalinization by the cobalt (III) complexes on the efficacy of the weakly basic drug, doxorubicin (dox) was also evaluated. This combination therapy of dox with cobalt (III) complexes resulted in enhanced apoptosis in A549 cells, as evidenced by elevated caspase 3/7 activity in treated groups. The study confirms the urease mimicking anticancer activity of cobalt (III) complexes by neutralizing the tumour microenvironment. This study will motivate the applications of transition metal-based enzyme mimics in targeting the tumour microenvironment for effective anticancer treatments.
Highlights
The last few decades have seen an upsurge in cancer research
We have explored an approach for indirectly altering results of the cytotoxicity of urease mimetic cobalt (III) complexes alone, and in combinathe tumour microenvironment by urease mimetic cobalt (III) complexes
Urease activity was long viewed as detrimental, and research was mainly focused on inhibiting the enzyme’s activity; the undesirable urease activity can be utilized to neutralize the acidity in tumour microenvironments, thereby leading to enhanced therapeutic efficiency
Summary
The last few decades have seen an upsurge in cancer research. Many developments and milestones have been achieved in discovering compounds with effective anticancer therapeutic properties. The research focus has shifted to develop target specific treatments These involve the design of target specific drug delivery agents such as using nanotechnology [3,4,5,6], immunotherapy [7,8], and more recently, antibody conjugation [9,10,11] to allow delivery of the drug molecule directly at the tumour site. These procedures are believed to improve drug efficacy while minimizing adverse side effects [12]. New treatment methods are in demand to fight this deadly disease
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