Nanotechnological approaches in cancer : the role of celecoxib and disulfiram

Introduction

The limited success of new drug approvals and the long development process of novel medicines are some of the problems found in the drug discovery field. Thus, the use of already approved drugs, originally developed for a specific therapeutic indication, in the treatment of other diseases is being increasingly studied [ ]. Herein, the pharmaceutical industry has found a niche and a possible solution for some issues, including the reduction of costs and duration of the stages in drug development associated to product approval ( Fig. 14.1 ). The redirection of “old drugs” has prompted advantages regarding the mechanism of action, identification of molecular targets, and pharmacological properties, including pharmacokinetics, pharmacodynamics, posology, toxicological profile, and drug–drug interactions, since most of the aforementioned parameters are already well established. Indeed, the main regulatory agencies have developed rescue programs of drugs that failed for a determined disease but may have a promising potential on other conditions [ ]. Drug repurposing can also be applied to combination therapy aiming at targeting different signaling pathways or receptors. In this case, drug dosage regimens may be tailored in order to minimize side effects while maintaining or potentiating drug efficacy. Preclinical studies regarding drug synergism or antagonism should be conducted, in order to prove biological efficacy at an early stage. In addition, the pharmacokinetic profile of the coadministration should also be assessed at least in vivo, as there may be potential clinical implications between drugs.

Despite having a higher probability of success, drug repurposing does not come without failure risk. Lack of clinical efficacy, organization within the industry, intellectual and legal barriers, and regulatory hurdles may impair the development of novel medicines based on old drugs (for additional details, please see Ref. [ ]). Focusing on clinical efficacy, the use of animal models does not always correlate well with clinical practice. As an example, topiramate has been suggested to have a positive impact on inflammatory bowel disease due to gene expression signatures and a rodent model but failed to prove its benefit on a cohort study [ ]. In fact, animal models can lack quality and/or validation. Furthermore, basic research is not always reproducible between research groups, thus creating an accuracy gap in knowledge transfer. A rudimental understanding of the target behavior in humans is also pointed as a common cause for translational failure [ ]. In order to reduce the probability of failure in clinical trials, the use of patient-derived xenograft (PDX) and genetically engineered mouse models is being encouraged, as they are more truthful representation of the pathologies. Overall, PDX models retain the main characteristics of the donor and are a stronger predictor of clinical outcomes than the conventional cell lines [ ].

Cases of a successful reposition include thalidomide (teratogenic for the fetus, currently used for refractory multiple myeloma), sildenafil (antianginal drug now used for the treatment of erectile dysfunction), exenatide (used in type II diabetes, now repurposed in the control of obesity issues), methotrexate (primarily developed for cancer, is also used for rheumatoid arthritis and psoriasis), and everolimus (an immunosuppressor drug used to avoid organ transplant rejection, is also used against neuroendocrine tumors of gastrointestinal (GI) or lung origin, or HER2-negative breast cancer) [ , ].

Oncology is one of the areas that has mostly benefited from drug repurposing, exhibiting favorable clinical trial outcomes [ , ]. The poor specificity and therapeutic response, which lead to dose-limiting side effects, impose the need to develop alternative therapies. Thus, the main groups of noncancer drugs that might offer effective treatment for cancer therapy are antidepressants, antipsychotic drugs, cardiovascular drugs, antimicrobiological agents, a drug for treating alcoholism, and nonsteroidal antiinflammatory drugs (NSAIDs) [ ].

This review provides a comprehensive overview of current repurposing nanotechnological approaches specifically concerning celecoxib (CXB) and disulfiram (DSF) for the treatment of neoplastic diseases.

NSAIDs as a class of repurposed drugs

NSAIDs are one of the pharmacotherapeutic groups most commonly prescribed for the symptomatic treatment of pain and fever. NSAIDs have sparked interest in the treatment of cancer, as a class of drug repurposing, due to their antiinflammatory properties [ ]. Indeed, cancer is linked to chronic inflammation. Therefore, the use of antiinflammatory drugs seems to play an important role in the treatment and prevention of cancer [ ]. NSAIDs may exert anticancer effects due to their ability to induce apoptosis, inhibit angiogenesis, and enhance cellular immune responses, which are signaling pathways common to both inflammation and carcinogenesis ( Fig. 14.2 ). Dysregulation of signaling pathways, aberrant expression of proinflammatory genes, and the release of cytokines in the tumor microenvironment (TME) are potential therapeutic targets for NSAIDs. Transforming growth factor-β, tumor-necrosis factor-α, interleukin (IL)-6, IL-10, nitric oxide synthase, reactive oxygen species (ROS), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) are some examples of proinflammatory mediators endogenously produced, which are involved in TME and inflammation [ ].

In fact, normal inflammation is a controlled process, due to the equilibrium between the production of antiinflammatory and proinflammatory cytokines. Nevertheless, the imbalance of factors and/or dysregulation of signaling pathways may lead to a chronic inflammation process that demands intervention. The prostanoids, including prostaglandins, prostacyclins, and thromboxanes, are a family of lipid mediators produced in response to diverse stimuli, and, acting in a paracrine or autocrine manner, they exert important roles either in normal physiology of the inflammation or disease processes. Prostaglandin production requires the conversion of arachidonic acid (AA) to the intermediate prostaglandin H2 catalyzed by the cyclooxygenase (COX) enzyme [ , ]. Two isoforms of the COX enzyme are described, COX-1 and COX-2. COX-1 is clinically important because of its constitutive expression in the major part of tissues, allowing the production of prostaglandins that helps in the maintenance of homeostasis; COX-2 is an induced enzyme with low expression in few tissues, exhibiting, however, a rapid expression in inflammatory processes, inducible by extracellular and intracellular stimuli, such as lipopolysaccharide, forskolin, IL-1, TNF-α, epidermal growth factor α, platelet-activating factor, interferon-γ, and endothelin [ , ]. Thus, the understanding of these mechanisms of action, regulation, and function has enabled the design and synthesis of COX inhibitors.

Depending on the generation of NSAIDs, these can be selective or not in the blocking of COX or prostaglandin endoperoxide H synthase. The first generation of NSAIDs, which includes aspirin, indomethacin, diclofenac, and sulindac, inhibits both COX-1 and COX-2 activity, while the second generation of NSAIDs includes, for example, CXB and rofecoxib, and it selectively inhibits COX-2 activity. Preclinical studies reflect the importance of targeting COX-2 in cancer, as it is highly expressed in several signaling pathways involved in invasion, proliferation, and angiogenesis [ ]. Among NSAIDs, the second generation stands out due to its selective COX-2 inhibition. Therefore, in repurposing strategies, the use of CXB, rofecoxib, valdecoxib, etoricoxib, or lumiracoxib is the natural and first choice. However, note that only CXB is approved by the Food and Drug Administration (FDA), as the remaining drugs were either withdrawn or not approved in the United States due to safety concerns. The potential approval of CXB for cancer treatment may be easily accomplished, if supported by solid clinical data, rather than the approval of other coxibs.

Celecoxib: physicochemical, pharmacokinetic, and pharmacodynamic parameters

CXB was the first approved drug belonging to the class of selective COX-2 inhibitors, approved by the FDA) in 1998. CXB inhibits the synthesis of prostaglandins by the inhibition of COX-2 in humans, having demonstrated efficiency to treat inflammatory diseases, such as rheumatoid arthritis and osteoarthritis, ankylosing spondylitis, acute pain, and primary dysmenorrhea. CXB is available in four dosage forms, respectively, 50, 100, 200, and 400 mg capsules. The dosage is different depending on the type of disease [ , ]. The dependence is related to the amount of AA, i.e., a higher amount of AA leads to increased prostaglandin production and, subsequently, a higher dose of NSAIDs is required for their effectiveness.

CXB physicochemical properties are a relevant information for the understanding of its pharmacokinetics and pharmacodynamics. Structurally, CXB is a diarylsubstituted pyrazole compound, also known as benzene sulphonamide. Chemically, it is termed as 4-[5-(4-methylphenyl)-3-trifluoromethyl-1H-pyrazoyl-1-yl] ( Fig. 14.3 ) having an empirical formula of H ₁₄ F ₃ N ₃ O ₂ S. It exhibits their action by specifically inhibiting COX-2 isoenzyme with a 5- to 50-fold selectivity. The sulphonamide moiety is the main group that defines its COX-2 selectivity and antiinflammatory activity. CXB is described in both crystalline and amorphous forms, wherein the crystalline form evidences less bioavailability than the amorphous one. CXB belongs to class II of Biopharmaceutical Classification System (BCS), characterized by low solubility and high permeability. Its poor water solubility is confirmed in several studies (c. 4.3 μg/mL) ( Table 14.1 ) [ ]. CXB is a drug that respects the Lipinski's “rule of five,” with good absorption and permeation in biological systems. It is a hydrophobic compound, with a log P of 3.5 [ ], and weakly acidic with a pKa of 11.1, ascribed to the ionization of the primary amine functional group.

The pharmacokinetic and pharmacodynamic properties of the CXB are summarized in Table 14.1 . This information is crucial for a rational newer repurposing. CXB is administered orally (once or twice a day, depending on the therapeutic indication) and quickly absorbed, exhibiting a maximum peak serum concentration between 2 and 4 h. CXB metabolism occurs essentially by the cytochrome P450 2C9 in the liver (97%), being described three metabolites, namely hydroxycelecoxib, carboxycelecoxib, and 1-O-glucuronide, with renal and fecal excretion. The unchanged form of CXB is also excreted in urine and feces in a low extent (<3%). CXB is used for antiinflammatory and analgesic effects by blocking the synthesis of different inflammatory prostanoids, including PGs and thromboxanes. These products are the end of fatty acid metabolism produced by COX enzymatic activity [ ]. These mediators are crucial for pathological and physiological processes, like pain, inflammation, glaucoma, osteoporosis, cardiovascular diseases, and cancer. Thus, the production of PGs is dependent on the accessibility of AA from the cellular phospholipids—secretory or cytoplasmic phospholipases. PG synthesis is stimulated by inflammatory cytokines and the consequent release of AA. Thus, the activation of COX-1 (encoded by PTGS ₁ ) and COX-2 (encoded by PTGS ₂ ) lead to the synthesis of prostanoids. COX converts AA in PGG ₂ , following reduction of PGG ₂ to PGH ₂ . The latter is converted into the active metabolites PGH ₂ , PGD ₂ , PGF ₂ α, prostacyclin (PGI ₂ ), and thromboxane (TXA ₂ ). These molecules interact with specific prostanoid G protein–coupled receptors, which mediate the physiological responses including blood pressure regulation, fever, inflammation, and GI protection.