Bioactivity-guided Isolation of TRAIL-Resistance-Overcoming Activity Compounds From the Leaves of Murraya exotica

Abstract

Fractionation of the leaf extract from Murraya exotica led to the successful isolation of 12 compounds (1-12) with TRAIL-resistance-overcoming activity. Xanthinosin (1), 11α, 13-dihydroxanthinin (2), 11β, 13-dihydroxanthinosin (3), 4α, 11α, 13-trihydroxanthuminol (4), desacetylxanthanol (5), and lasidiol p-methoxybenzoate (6) were sesquiterpenes isolated from this plant for the first time, and 3 was isolated from natural sources for the first time. Among them, compounds 1 and 5 showed strong TRAIL-resistance-overcoming activity, but their mechanisms have already been revealed. Furthermore, dihydroxanthinin (2), 1, 5-dicaffeoylquinic acid (7), and (-) loliolide (8), which belong to different phytochemical groups, were investigated for their effects on increasing apoptosis induction to overcome TRAIL resistance using Western blot analysis. The results demonstrated that 2, 7, and 8 promoted TRAIL-induced apoptosis by increasing the expression of several proapoptotic markers, including cleaved caspases −3 and −8, and suppressing anti-apoptotic protein Bcl-2.

Isolation of Various Flavonoids with TRAIL Resistance-Overcoming Activity from Blumea lacera

“…Although the compounds have the same flavonoid skeleton, the strength of the TRAIL resistance-overcoming activity depends on the substituents. Among the isolated flavonoids, bonanzin (2) and cirsilineol (7) exhibited strong TRAIL resistance-overcoming activity, with IC 50 values of 10.7 µM and 5.9 µM, respectively.…”

“…The EtOAc layer was also fractionated to obtain compounds 12-14 (Figure 1). Detailed NMR and mass spectrometry analysis identified the isolated compounds as pectolinargenin (1) [10], bonanzin (2) [11], velutin (3) [12], chrysosplenol B (4) [13], chrysosplenol C (5) [13], 4',5-dihydroxy-3',7-dimethoxyflavone (6) [14], cirsilineol (7) [15], eupatilin (8) [16], 3-demethoxycentaureidin (9) [17], jaceidin (10) [18], centaureidin (11) [19], patuletin 3-O-β-D-glucopyranoside (12) [20], patulitrin (13) [21], 6-methoxykaempferol 3-O-β-D-glucopyranoside ( 14) [22], 3-oxostigmasta-4,22E-diene (15) [23], 9-oxo-10E,12Zoctadecadienoic acid (16) [24], 3-hydroxy-octadeca-4E,6Z-dienoic acid (17) [25], and aurantiamide acetate (18) [26].…”

“…Most of the isolated flavonoids exhibited TRAIL resistance-overcoming activity (Figure 2). Bonanzin (2) and cirsilineol (7) had particularly strong TRAIL resistance-overcoming activity, with IC50 values of 10.7 μM and 5.9 μM in the presence of TRAIL (100 ng/mL), whereas compounds 2 and 7 had IC50 values of 26.1 μM and 20.7 μM without TRAIL, respectively (Figure 2). There have been no reports on the TRAIL resistance-overcoming activity of these compounds [27].…”

“…We previously reported some naturally derived compounds with TRAIL resistanceovercoming activity [7,8]. In this study, we describe the isolation of eighteen compounds from the whole plant of Blumea lacera and report their TRAIL resistance-overcoming activity.…”

Curcumin Sensitises Cancerous Kidney Cells to TRAIL Induced Apoptosis via Let-7C Mediated Deregulation of Cell Cycle Proteins and Cellular Metabolism

“…Thus, there is an unmet need to restore the sensitivity of cancer cells to TRAIL [ 10 , 11 ]. Much research has been conducted to achieve TRAIL sensitization using combinatorial regimens of TRAIL with various compounds including natural products [ 12 , 13 , 14 , 15 ]. One of the successful approaches involved targeting cancer cells with a combinatorial regimen of curcumin and TRAIL [ 16 , 17 ].…”