Abstract
Cancer stem cells (CSCs) are thought to be responsible for cancer relapse. CSCs are a subtype of cancer cells with the ability to differentiate, self-renew, and form secondary or tertiary tumors. Current cancer treatments—including chemotherapy, radiation, and surgery—effectively remove bulk cancer cells but are unable to eliminate CSCs. Here, we present the synthesis, characterization, and anti-CSC properties of a cobalt(III)–cyclam complex bearing two tolfenamic acid moieties, 3. Notably, 3 displays sub-micromolar potency towards breast CSCs and bulk breast cancer cells. Detailed mechanistic studies show that 3 is taken up readily by breast CSCs, enters the nucleus, causes DNA damage, and induces caspase-dependent apoptosis. Furthermore, 3 inhibits cyclooxygenase-2 (COX-2) expression in CSCs. The mechanism of action of 3 is similar to that of a naproxen-appended cobalt(III)–cyclam complex, 1 recently reported by our group. The advantage of 3 over 1 is that it has the potential to remove whole tumor populations (bulk cancer cells and CSCs) with a single dose.
Highlights
Cancer is the third highest cause of death in the developed world [1]
Cancer reoccurrence has been heavily linked to the existence of a small subpopulation of tumor cells called cancer stem cells (CSCs) [3,4]
It should be noted that several metal–nonsteroidal anti-inflammatory drug (NSAID) have been previously reported, and their binding to biomolecules such as DNA and human serum albumin (HSA) has been well characterized using to biomolecules such as DNA and human serum albumin (HSA) has been well characterized using spectroscopic methods [48,49,50,51,52]
Summary
Cancer is the third highest cause of death in the developed world [1]. Despite significant improvements in traditional cancer therapies (chemotherapy, radiation therapy, and surgery), long-term cures for cancers of all tissue types remains out of reach [2]. CSCs exhibit cancer and stem-like properties and self-renew, divide asymmetrically, and evade standard treatments [5,6,7,8]. These traits endow CSCs with the ability to control tumor initiation, propagation, and metastasis [9,10]. Octahedral cobalt(III) complexes containing cytotoxic can potentially block CSC growth. The rationale for the attachment of tolfenamic acid to the cobalt(III)–cyclam core is two-fold; bulk breast cancer cells in vitro. The rationale for the attachment of tolfenamic acid to the cobalt(III)– It increases lipophilicity of the complex, which facilitates cell uptake, it inhibits. The CSC cytotoxicity and mechanism discussed in detail, and compared to of action of 3 will be discussed in detail, and compared to 1
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