Transdermal delivery of pharmacologically active agents has been extensively studied for the past 40 years. Despite the strong efforts, currently, only about 40 products are in market on about 20 drug molecules, due to the requirements that the patch area should be small enough for the patients to feel comfortable, and to the barrier properties of the stratum corneum. Various approaches to overcome the barrier function of skin through physical and chemical means have been broadly studied. The development of an effective transdermal delivery system is dictated by the unique physicochemical property each drug molecule possesses. In this review, we have summarized various physical and chemical approaches for transdermal flux enhancement, including the application of electricity, ultrasound, microneedle and chemical enhancers. Pressure sensitive adhesive such as acrylics, rubbers and silicones are described together with recent developments. Factors affecting dosage form design, particularly for drug in adhesive system, like adhesion and crystallization are also discussed.

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Acquisition of resistance to tamoxifen is a critical therapeutic problem in breast cancer patients. Epithelial-mesenchymal transition (EMT), where cells undergo a developmental switch from a polarized epithelial phenotype to a highly motile mesenchymal phenotype, is associated with invasion and motility of cancer cells. Here, we found that tamoxifen-resistant (TAMR)-MCF-7 cells had undergone EMT, as evidenced by mesenchymal-like cell shape, downregulation of basal E-cadherin expression, and overexpression of N-cadherin and vimentin, as well as increased Snail transcriptional activity and protein expression. Given the roles of glycogen synthase kinase (GSK)-3b and nuclear factor (NF)-κB in Snail-mediated E-cadherin deregulation during EMT, we examined the role of these signaling pathways in the EMT of TAMR-MCF-7 cells. Both Ser9-phosphorylated GSK-3b (inactive form) and NF-κB reporter activity were increased in TAMR-MCF-7 cells, as was activation of the phosphatase and tensin homolog depleted on chromosome ten ( B reast cancer is the most common malignancy in Western women. Hormone-dependent control of growth is a characteristic of breast cancer. Ovarian steroid hormones, including estrogen, are essential for both mammary gland development and breast carcinoma formation.(1,2) Hence, the administration of anti-estrogens to reduce breast tumor growth has played a key role in the endocrine therapy of breast cancer. Tamoxifen (TAM), a non-steroidal anti-estrogen, is the most widely used anti-estrogen in estrogen receptor-positive breast cancer patients.(3) Despite an initial response to TAM, the majority of patients will ultimately relapse and present with disease progression. Therefore, resistance to TAM is a major challenge in the management of breast cancer patients. (4,5) To mimic this condition, we and others have established an MCF-7-derived TAM-resistant cell line (TAMR-MCF-7 cells) by long-term (>9 months) culture of MCF-7 cells with 4-hydroxytamoxifen. (6,7) Epithelial tumors metastasize by initially invading the adjacent tissues, a process involving the loss of their cell-cell adhesions and the acquisition of migratory capabilities. These processes coincide with phenotype changes associated with epithelialmesenchymal transitions (EMT), similar to those that take place during certain steps of embryonic development. (8) EMT is involved in the efficient invasion and motility of cancer cells, because migration of single cancer cells is elicited by using either mesenchymal or amoeboid phenotypes.(9,10) The invasive and metastatic phenotype is associated with downregulation of E-cadherin expression.(11) Several mechanisms have been implicated in the regulation of E-cadherin expression during tumor progression, including genetic, epigenetic, and transcriptional changes. (12,13)

Phenolic constituents of virgin olive oil are reported to have antitumor activity. However, the underlying molecular mechanisms and specific target proteins of virgin olive oil remain to be elucidated. Here, we report that dialdehydic form of decarboxymethyl ligstroside aglycone (p-HPEA-EDA), a phenolic compound of virgin olive oil, inhibits tumor promoter-induced cell transformation in JB6 Cl41 cells and suppress cyclooxygenase-2 (COX-2) and tumorigenicity by adenosine monophosphate-activated protein kinase (AMPK) activation in HT-29 cells. p-HPEA-EDA inhibited 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced phosphorylation of extracellular signal-regulated kinases 1/2 and p90RSK in JB6 Cl41 cells, resulting in the inhibition of cell proliferation, activator protein-1 transactivation and cell transformation promoted by TPA. Moreover, p-HPEA-EDA strongly inhibited the cell viability and COX-2 expression by activation of AMPK activity in HT-29 cells, resulted from depletion of intracellular adenosine triphosphate. p-HPEA-EDA-induced activation of caspase-3 and poly-adenosine diphosphate-ribose polymerase, phosphorylation of p53 (Ser15) and DNA fragmentation in HT-29 cells, leading to apoptosis. Importantly, p-HPEA-EDA suppressed the colony formation of HT-29 cells in soft agar. In contrast, Compound C, an AMPK inhibitor, and Z-DEVD-FMK, a caspase-3 inhibitor, blocked the p-HPEA-EDA-inhibited colony formation in HT-29 cells. In vivo chorioallantoic membrane assay also showed that p-HPEA-EDA-inhibited tumorigenicity of HT-29 cells. These findings revealed that targeted activation of AMPK and inhibition of COX-2 expression by p-HPEA-EDA contribute to the chemopreventive and chemotherapeutic potential of virgin olive oil against colon cancer cells.

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