Abstract
Previous studies have shown that intensive macropinocytosis occurs in cancer cells and neutral red (NR) is noted for its capability to enter into the cell massively through a process mimetic to macropinocytosis. In addition, trans-cinnamic acid (tCA) has been found to be an inhibitor of histone deacetylase (HDAC). In the present study, cinnamoylphenazine (CA-PZ) that consists of NR and tCA moieties was synthesized and evaluated. As shown, CA-PZ massively entered into colon carcinoma HT-29 cells and pancreatic carcinoma MIA PaCa-2 cells and this entry was blocked by 5-(N-ethyl-N-isopropyl) amiloride (EIPA, an inhibitor of macropinocytosis), indicating a macropinocytosis-mediated uptake. Furthermore, CA-PZ markedly increased the protein expression levels of acetyl-H3, acetyl-H4 and p21 in HT-29 cells and MIA PaCa-2 cells. CA-PZ significantly inhibited the growth of colon carcinoma HT-29 and pancreatic carcinoma MIA PaCa-2 xenografts. By in vivo imaging, CA-PZ displayed prominent accumulation in the tumor xenografts. The study indicates that the newly synthesized CA-PZ acts as an HDAC inhibitor in association with intensive macropinocytosis-mediated intracellular delivery in cancer cells. The use of neutral red for preparation of chimeric molecules with the attribute of macropinocytosis-mediated intracellular delivery might open an alternative way for development of HDAC inhibitors.
Highlights
Recent studies have demonstrated that macropinocytosis is significantly activated in a variety of cancer cells
The present study indicates that CA-PZ is active as histone deacetylase (HDAC) inhibitor in association with intensive macropinocytosis-mediated entry into cancer cells
CA-PZ markedly decreased the protein expression levels of acetyl-H3, acetyl-H4 and p21, which was consistent with effects of the known HDAC inhibitor trichostatin A (TSA), indicating that CA-PZ is an active HDAC inhibitor
Summary
Recent studies have demonstrated that macropinocytosis is significantly activated in a variety of cancer cells. Macropinocytosis is exploited by a range of pathogens for cellular invasion and avoidance of immune surveillance [1]. Macropinocytosis provides a unique pathway for intracellular entry with a form of bulk uptake and can efficiently and rapidly internalize the carried substances [2]. Macropinocytosis is markedly enhanced in K-rastransformed pancreatic carcinoma cells; apparently, it may represent an important route of tumor nutrient uptake [3]. Besides playing important roles in a range of physiological processes, macropinocytosis is highly relevant to cell migration and tumor metastasis [4, 5]. Macropinocytosis could be induced by the stimulation of epidermal growth factor receptor (EGFR), leading to the enhancement of cellular uptake [6]. Macropinocytosis may be stimulated by a nucleolin-dependent mechanism [7]
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