2‐O‐Octadecylascorbic acid represses RhoGDIβ expression and ameliorates DNA damage‐induced abnormal spindle orientations

Abstract

The appropriate regulation of spindle orientation maintains proper tissue homeostasis and avoids aberrant tissue repair or regeneration. Spindle misorientation due to imbalance or improper functioning leads to a loss of tissue integrity and aberrant growth, such as tissue loss or overgrowth. Pharmacological manipulation to prevent spindle misorientation will enable a better understanding of how spindle orientation is involved in physiological and pathological conditions and will provide therapeutic possibilities to treat patients associated with abnormal tissue function caused by spindle misorientation. N‐terminal‐deleted Rho guanine nucleotide dissociation inhibitor β (RhoGDIβ/RhoGDI2/LyGDI) produced by caspase‐3 activation perturbs spindle orientation in surviving cells following exposure to either ionizing radiation or UVC. Thus, presumably, RhoGDIβ cleaved by caspase‐3 activation acts as a determinant of radiation‐induced spindle misorientation that promote aberrant tissue repair due to deregulation of directional organization of cell population and therefore becomes a potential target of drugs to prevent such response. The objective of this study was to screen and identify chemicals that suppress RhoGDIβ expression. We focused our attention on ascorbic acid (AA) derivatives because of their impact on the maintenance of skin tissue homeostasis. Here, we screened for AA derivatives that suppress RhoGDIβ expression in HeLa cells and identified a lipophilic derivative, 2‐O‐octadecylascorbic acid (2‐OctadecylAA), as a novel RhoGDIβ inhibitor that ameliorated ionizing radiation‐induced abnormal spindle orientations. Among all examined AA derivatives, which were also antioxidative, the inhibition activity was specific to 2‐OctadecylAA. Therefore, this activity was not due to simple antioxidant properties. 2‐OctadecylAA was previously shown to prevent hepatocellular carcinoma development. Our findings suggest that the anticarcinogenic effects of 2‐OctadecylAA are partly due to RhoGDIβ inhibition mechanisms by which spindle orientation perturbations are attenuated. Thus, the molecular targeting features of RhoGDIβ warrant its further development for the treatment or control of spindle orientation abnormalities that affect epithelial homeostasis.

Facial Treatment with 3-O-Cetyl Ascorbic Acid for Improvement of Skin Texture: Uptake, Effectiveness, and In Vitro Carcinogenicity Assessment

“…We recently discovered that 2-O-octadecylascorbic acid (2-OctadecylAA) prevents misoriented cell divisions with repression of RhoGDIβ expression [42]. Moreover, 2-OctadecylAA is lipophilic, as is 3-CetylAA.…”

“…Moreover, 2-OctadecylAA is lipophilic, as is 3-CetylAA. Therefore, a possible mechanism behind the effects of 3-CetylAA on skin texture may comprise the prevention of misoriented cell divisions, which is mediated through RhoGDIβ repression [42,43]. Another possible mechanism may involve the elimination of unfit keratinocytes, which is mediated through type XVII collagen synthesis [44].…”

“…It is important to determine whether 3-CetylAA is carcinogenic and has synergistic effects with UV irradiation. Here, we tested 10 µM 3-CetylAA for these effects because another lipophilic AA derivative, 2-OctadecylAA, was observed to have in vitro biological activities in the same concentration range [42]. Using a BALB/c 3T3 A31-1-1 cell transformation assay system, we demonstrated that 10 µM 3-CetylAA has no transformation-initiation activity, and also that 10 µM 3-CetylAA does not potentiate the UVC-induced killing effects and the UVC-induced transformation frequency.…”

Neurite Outgrowth-Promoting Compounds from the Petals of Paeonia lactiflora in PC12 Cells

“…The DPPH radical scavenging activity was evaluated by modifying the method previously reported [40]. The DPPH radical scavenging assay was carried out in a 96-well plate.…”

Tetrahexyldecyl Ascorbate (THDC) Degrades Rapidly under Oxidative Stress but Can Be Stabilized by Acetyl Zingerone to Enhance Collagen Production and Antioxidant Effects

“…These observations have prompted the development of topical formulations with the goal of directly delivering AA to skin to achieve cosmetic or therapeutic effects. Topical AA delivery has been reported to improve some aspects of intrinsic skin aging [11][12][13], although stronger evidence supports a role for AA in the antioxidant-mediated prevention of extrinsic aging due to UV radiation exposure [14][15][16]. Further evidence has supported a role for topically-applied AA or AA-derivatives for treatment of wound healing and scar formation [17][18][19], allergic contact dermatitis [20], hyperpigmentation [21][22][23][24][25], atopic dermatitis [26,27], striae distensae [28], cutaneous malignancies [29][30][31], and psoriasis [32].…”