Simultaneous Targeting of COX-2 and AKT Using Selenocoxib-1-GSH to Inhibit Melanoma

Abstract

Melanoma is a highly metastatic and deadly disease. An agent simultaneously targeting COX-2, PI3K/Akt and MAPK signaling pathways that are deregulated in up to 70% of sporadic melanoma might be an effective treatment but no agent of this type exists. To develop a single drug inhibiting COX-2 and PI3K/Akt signaling (and increasing MAPK pathway activity to inhibitory levels as a result of Akt inhibition), a selenium-containing glutathione (GSH) analog of celecoxib, called selenocoxib-1-GSH was synthesized. It killed melanoma cells with an average IC50 of 7.66 µmol/L compared to control celecoxib at 55.6 µmol/L. The IC50 range for normal cells was 36.3–41.2 µmol/L compared to 7.66 µmol/L for cancer cells. Selenocoxib-1-GSH reduced xenografted tumor development by ~70% with negligible toxicity by targeting COX-2, like celecoxib, and having new inhibitory properties acting as a PI3K/Akt inhibitor (and MAPK pathway activator to inhibitory levels due to Akt inhibition). The consequence of this inhibitory activity was an ~80% decrease in cultured cell proliferation and a ~200% increase in apoptosis following 24 hours treatment with 15.5 µmol/L of drug. Thus, this study details development of selenocoxib-1-GSH, which is a non-toxic agent that targets the COX-2 and PI3K/Akt signaling pathways in melanomas to inhibit tumor development.

Novel Heteroaryl Selenocyanates and Diselenides as Potent Antileishmanial Agents

“…Melting points (mp) were determined with a Mettler FP82ϩFP80 apparatus (Greifense, Switzerland) and are not corrected. The 1 H nuclear magnetic resonance (NMR) and 13 C NMR spectra were recorded on a Bruker 400 Ultrashield spectrometer (Rheinstetten, Germany) using TMS (tetramethylsilane) as the internal standard. The infrared (IR) spectra were obtained on a Thermo Nicolet FT-IR Nexus spec- trophotometer with KBr pellets.…”

“…Their purity was assessed by TLC and elemental analyses, and their structures were identified from spectroscopic data. IR, 1 H NMR, 13 C NMR, mass spectrometry, and elementary analysis methods were used for structure elucidation (Fig. 2).…”

“…Several reports have shown vast and miscellaneous types of structures applying this approach, resulting in very promising antitumoral compounds in preclinical models (12,13). Recently, our research group has been using this rational design in order to obtain new derivatives with potent and selective antileishmanicidal activity.…”

The Critical Role of PTEN/PI3K/AKT Signaling Pathway in Shikonin-Induced Apoptosis and Proliferation Inhibition of Chronic Myeloid Leukemia

“…The major substrate of PTEN is phosphatidylinositol-3, 4, 5-triphosphate (PIP3), which is produced by the action of phosphoinositide-3-kinase (PI3K) [10]. The PI3K/AKT signaling pathway plays an important role in the development of resistance to carcinoma therapy, and inhibition of the PI3K/AKT signaling pathway may suppress cancer cell growth and induce apoptosis in various cancers [11][12][13]. PTEN is the main negative regulator of the PI3K/AKT signaling pathway and is implicated in regulating proliferation and survival of T-cell progenitors [14].…”

Nanolipolee-007, a Novel Nanoparticle-Based Drug Containing Leelamine for the Treatment of Melanoma

“…Using a combination of protein arrays and systems biology followed by validation studies, leelamine was found to inhibit the PI3K/Akt, STAT3 and MAPK pathways by disrupting cancer cell cholesterol transport. These are key driver pathways in melanoma cells constitutively activated in 50 to 70% of melanomas, functioning to reduce cellular apoptosis, increase proliferation and aid the invasive processes promoting melanoma progression (14-16). …”