A Novel Curcumin-Mycophenolic Acid Conjugate Inhibited Hyperproliferation of Tumor Necrosis Factor-Alpha-Induced Human Keratinocyte Cells

Abstract

Curcumin (CUR) has been used as adjuvant therapy for therapeutic application in the treatment of psoriasis through several mechanisms of action. Due to the poor oral bioavailability of CUR, several approaches have been developed to overcome the limitations of CUR, including the prodrug strategy. In this study, CUR was esterified with mycophenolic acid (MPA) as a novel conjugate prodrug. The MPA-CUR conjugate was structurally elucidated using FT-IR, 1H-NMR, 13C-NMR, and MS techniques. Bioavailable fractions (BFs) across Caco-2 cells of CUR, MPA, and MPA-CUR were collected for further biological activity evaluation representing an in vitro cellular transport model for oral administration. The antipsoriatic effect of the BFs was determined using antiproliferation and anti-inflammation assays against hyperproliferation of tumor necrosis factor-alpha (TNF-α)-induced human keratinocytes (HaCaT). The BF of MPA-CUR provided better antiproliferation than that of CUR (p < 0.001). The enhanced hyperproliferation suppression of the BF of MPA-CUR resulted from the reduction of several inflammatory cytokines, including IL-6, IL-8, and IL-1β. The molecular mechanisms of anti-inflammatory activity were mediated by an attenuated signaling cascade of MAPKs protein, i.e., p38, ERK, and JNK. Our results present evidence for the MPA-CUR conjugate as a promising therapeutic agent for treating psoriasis by antiproliferative and anti-inflammatory actions.

Efficacy and safety of curcumin in psoriasis: preclinical and clinical evidence and possible mechanisms

“…et al, 2019 ; Wang ZJ. et al, 2019 ; Zhang et al, 2020 ; Yuyun et al, 2021 ) used HaCaT cells, which were treated with different concentrations of CUR or CUR combined with different preparations. Psoriasis related mechanisms in keratinocytes were induced using vascular endothelial growth factor ( Wang ZJ.…”

“…Psoriasis related mechanisms in keratinocytes were induced using vascular endothelial growth factor ( Wang ZJ. et al, 2019 ; Zhang et al, 2020 ), IL-22 ( Zhao et al, 2015 ), IMQ ( Varma et al, 2017 ), TNF-α ( Cho et al, 2007 ; Sun et al, 2012 ; Yuyun et al, 2021 ), nanostructured lipid dispersions ( Esposito et al, 2015 ), and pSG5.HA.mZac1 ( Hung et al, 2015 ). Supplementary Tables S2, S3 summarize the characteristics of the included preclinical studies.…”

A Stability-Indicating Ultra Performance Liquid Chromato-Graphic (UPLC) Method for the Determination of a Mycophenolic Acid-Curcumin Conjugate and Its Applications to Chemical Kinetic Studies

“…320.3 g/mol) was obtained from AK Scientific (Union City, CA, USA). The CUR and MPA-CUR (purity > 98% by HPLC) were prepared and characterized in our laboratory using the previously published method [ 2 , 9 ]. The analytical grades of formic acid and dimethyl sulfoxide (DMSO) were bought from Carlo Erba (Parc d’affaire des Portes, Val de Reuil, France).…”

“…A mutual prodrug strategy derives several benefits from having two active compounds in one molecule [ 1 ]. We recently synthesized a novel mycophenolic acid-curcumin (MPA-CUR) conjugate as a prodrug of mycophenolic acid (MPA) and curcumin (CUR) ( Figure 1 ) [ 2 ]. The bioavailable fraction (BF) of MPA-CUR across Caco-2 cells showed better anti-psoriatic and anti-inflammatory effects than that of CUR in a TNF-α-induced HaCaT cell model [ 2 ], suggesting MPA-CUR as a potential candidate for psoriasis treatment [ 2 ].…”

“…We recently synthesized a novel mycophenolic acid-curcumin (MPA-CUR) conjugate as a prodrug of mycophenolic acid (MPA) and curcumin (CUR) ( Figure 1 ) [ 2 ]. The bioavailable fraction (BF) of MPA-CUR across Caco-2 cells showed better anti-psoriatic and anti-inflammatory effects than that of CUR in a TNF-α-induced HaCaT cell model [ 2 ], suggesting MPA-CUR as a potential candidate for psoriasis treatment [ 2 ]. Because MPA-CUR requires bioconversion, giving parent molecules to exert anti-psoriatic activity, chemical kinetic studies of MPA-CUR are useful in determining the stability of MPA-CUR under physiological conditions.…”