Aerosol Administration of Phospho-Sulindac Inhibits Lung Tumorigenesis

Abstract

Phospho-sulindac (PS) is a sulindac derivative with promising anticancer activity in lung cancer, but its limited metabolic stability presents a major challenge for systemic therapy. We reasoned that inhalation delivery of PS might overcome first-pass metabolism and produce high levels of intact drug in lung tumors. Here, we developed a system for aerosolization of PS and evaluated the antitumor efficacy of inhaled PS in an orthotopic model of human non-small cell lung cancer (A549 cells). We found that administration by inhalation delivered high levels of PS to the lungs and minimized its hydrolysis to less active metabolites. Consequently, inhaled PS (6.5mg/kg) was highly effective in inhibiting lung tumorigenesis (75%, p<0.01) and significantly improved the survival of mice bearing orthotopic A549 xenografts. Mechanistically, PS suppressed lung tumorigenesis by 1) inhibiting EGFR activation, leading to profound inhibition of Raf/MEK/ERK and PI3K/AKT/mTOR survival cascades; 2) inducing oxidative stress, which provokes the collapse of mitochondrial membrane potential and mitochondria-dependent cell death; and 3) inducing autophagic cell death. Our data establish that inhalation delivery of PS is an efficacious approach to the prevention of lung cancer, which merits further evaluation.

Phospho-NSAIDs Have Enhanced Efficacy in Mice Lacking Plasma Carboxylesterase: Implications for their Clinical Pharmacology

“…The results presented here, as well as in our previous studies, reaffirmed our hypothesis that phospho-NSAIDs are a class of pharmacologically disparate identities from the NSAIDs from which they are derived (8, 9,14, 23), and that carboxylesterase-mediated hydrolysis leads to their inactivation. In this regard, phospho-NSAIDs are distinct from conventional ester prodrugs, such as irinotecan (24–26), capecitabine (27–29) and LY2334737 (30), which are bioactivated upon cleavage with carboxylesterases.…”

“…Given the impact of murine Ces1c on the pharmacological activity of phospho-NSAIDs and that the human plasma does not have carboxylesterase activity, our findings provide a biological rationale for the use of Ces1c knockout mice for the pharmacokinetic and efficacy evaluation of this class of anticancer agents, as these mice may represent a more accurate model of human drug metabolism. Phospho-NSAIDs are a novel class of anticancer drugs that have demonstrated strong inhibitory effects in preclinical models of human cancers (6,13,16, 23). A common structural feature of these phospho-modified drugs is the presence of a carboxylic ester bond linking the parent NSAIDs to a phospho-head group via a linker; and the integrity of this linkage is critical for the pharmacological activity of the drugs.…”

“…Whilst conventional NSAIDs are thought to suppress carcinogenesis in part via the inhibition of cyclooxygenase-2 (32), chemical modification with the phospho-moiety abrogates their ability to inhibit this enzyme (8). Several COX-independent molecular targets of phospho-NSAIDs have emerged in recent studies, such as the epidermal growth factor receptor (23), the thioredoxin system (11), and NF-ΚB (33). …”

NSAIDs Inhibit Tumorigenesis, but How?

“…Additional sulindac derivatives have since been developed, for example, that selectively inhibit PDE5 and have antitumor activity without inhibiting COX-1 or COX-2 (50). Recent efforts to develop improved chemopreventive agents also include the synthesis of phospho-derivatives that lack COX-inhibitory activity, such as phospho-sulindac and phospho-aspirin, but display high safety and efficacy in preclinical models of various cancer types (101, 102). Furthermore, the sulindac derivative K-80003 that selectively targets RXRα (82) and celecoxib derivatives OSU-03012 (103) and dimethyl-celecoxib (104) that inhibit PDK-1 without COX inhibition, represent other examples of separating COX-inhibitory activity and antitumor efficacy.…”

Chemoprevention of Lung Carcinogenesis by Dietary Nicotinamide and Inhaled Budesonide

“…Previously our group has published on budesonide, five fluorouracil, and difluoromethylornithine (DFMO) as effective agents for lung cancer prevention (41,45). Others have shown phosphor-sulindac, Polyphenon E, and retinoids are also efficacious in lung cancer prevention (46)(47)(48). Translationally, a human phase IIb study was conducted with inhaled budesonide at 1,600 mcg/day for 6 months and the trial result did not reverse histology in endobronchial lesions, often squamous carcinoma precursor lesions accessible by standard bronchoscopy (49).…”