The potent anti-proliferative and pro-apoptotic actions of tocotrienols (T3) against cancer, but not normal tissues, have been hampered by their limited systemic bioavailabilty. Recent expansive development of diverse nanoemulsion (NE) vehicles emphasized their vast potential to improve the effective dosing of different clinical and experimental drugs of lipophilic nature, such as T3. The emphasis of the present work is to develop a pharmaceutically scalable, low-energy nano-emulsification approach for optimized incorporation of T3-rich palm oil (Tocomin®), possessing anticancer activity as a potential cutaneous delivery platform for adjunctive therapy of skin carcinomas, either alone or in combination with other chemotherapeutic agents. Different Tocomin®-NEs, obtained with different homogenization strategies, were screened based on physicochemical uniformity (droplet size, charge and polydispersity) and subjected to stress physical stability testing, along with chemical content analysis (≥90% Tocomin® - incorporation efficiency). Adopted hybrid nano-emulsification of Tocomin®, correlated with highest preservation of DPPH-radical scavenging capacity of active T3 in prototype formulation, Tocomin®-NE, which effectively permeated diffusion cell membranes 4-folds higher than propyleneglycol (PG)-admixed Tocomin® control. Against two different cell models of human cutaneous carcinoma, Tocomin®-hybrid NE demonstrated significantly stronger cytotoxic profiles (p ≤ 0.01), visible in both concentration- and time- dependent manners, with at least 5-folds lower IC50 values, compared to those estimated for the closest Tocomin®-control. The proposed hybrid nano-emulsified formulation of Tocomin® provides simple and stable delivery platform, for effective topical application against keratinocyte tumors.
Gap junctions are intercellular channels that comprise connexin proteins such as Cx43 (connexin43). The level of gap junctional intercellular communication can be regulated by Cx43 turnover mediated through various degradation pathways. The UbL (ubiquitin-like) domain-UBA (ubiquitin-associated) domain protein, CIP75 (connexin43-interacting protein of 75 kDa), regulates the proteasomal degradation of Cx43. Subcellular fractionation studies indicated that CIP75 interacts with Cx43 that is localized to the membrane of the ER (endoplasmic reticulum). This Cx43-CIP75 complex also contained the proteasomal subunits S2/Rpn1 and S5a/Rpn10, as demonstrated by co-immunoprecipitation. The deliberate misfolding of Cx43, induced by DTT, led to enhanced CIP75 binding. Reducing CIP75 levels by shRNA-mediated knockdown diminished the association of Cx43 with the proteasome, but still allowed for Cx43 ER dislocation and degradation. These results suggested that CIP75 is essential for the interaction of Cx43 and the proteasome, but that alternate compensatory mechanisms exist to supplement the degradation normally facilitated by CIP75.
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