**Author details**

166 Apoptosis and Medicine

**4. Conclusion** 

patients experienced a partial or complete response and five patients (28%) demonstrated stable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) [86].

Although many encouraging results of in vitro and in vivo studies suggest polyphenolic compounds as a promising candidate for cancer therapy, either alone or in combination with current anticancer drugs, the therapeutic applications of these compounds in humans are limited by their high metabolic instability as well as poor absorption and bioavailability [1, 7, 8, 20, 87]. In this regard, the selective delivery of nanotechnology-based formulations of these polyphenolic compounds to tumors, alone or in combination with other anticancer drugs, has been of great interest [7, 26, 88]. For instance, pegylated liposomal quercetin was shown to significantly improve its solubility and bioavailability and be a potential application in the treatment of tumor based on a study using CT26 (a mouse colorectal carcinoma cell line), LL/2 (Lewis lung cancer cell line) and H22 (a hepatoma cell line) xenograft mice [88]. Furthermore, diverse curcumin formulations have been developed with different nanotechnology consisting of its encapsulation or conjugation with nanoparticles, polymeric micelles or liposomes to improve its stability, bioavailability and specific and sustained delivery into cancer cells and, consequently, its anticarcinogenic effects [7]. In particular, the systemic administration of gemcitabine plus polymeric micelle-encapsulated curcumin formulation enhanced greater bioavailability in plasma and tissues as compared to that of free curcumin in xenograft models of human pancreatic cancer established in athymic mice [89]. In consequence, the combinatory administration efficiently block tumor growth and metastases in this animal model of pancreatic cancer. Furthermore, an inhibition of NF-κB and its targeted genes are implicated in the tumor growth inhibition [89]. Therefore, the use of nanotechnology-based formulations of polyphenolic compounds and their novel chemical analogs probably represents a potential alternative strategy of great clinical interest for overcoming the high metabolic instability and poor bioavailability of these compounds,

which are among the principal factors limiting their therapeutic applications.

A striking global research on substances derived from natural products including polyphenolic compounds is being explored to understand the detailed mechanisms of their chemopreventive, antitumoral and chemosensibilizing activities against various types of aggressive and recurrent cancers. Besides the involvement of altered redox status in apoptosis induction triggered by these compounds, anti-inflammatory effects, antiangiogenesis, anti-invasiveness and induction of differentiation are well known to be implicated in their broad biological functions. It is worthy of note that flavonoids have been revealed to inhibit the function of ATP-binding cassette transporters such as multidrug resistance-associated proteins as well as P-glycoprotein [90], similar to our recent study [91]. On the other hand, a recent study demonstrated that berry anthocyanins, such as cyanidin-3-galactosidee, and cyanidin-3-glucoside as well as peonidin-3-glucosid, exhibit affinities for the efflux transporters breast cancer resistance protein (BCRP) and consequently may be actively transported out of intestinal tissues and endothelia [92]. However, the same report also demonstrated that some berry anthocyanins and Bo Yuan, Masahiko Imai, Hidetomo Kikuchi, Shin Fukushima, Shingo Hazama, Takenori Akaike, Yuta Yoshino, Kunio Ohyama and Hiroo Toyoda *Department of Clinical Molecular Genetics, School of Pharmacy, Tokyo University of Pharmacy & Life Sciences, Hachioji, Tokyo, Japan* 

## Xiaomei Hu

*National Therapeutic Center of Hematology of Traditional Chinese Medicine, XiYuan Hospital, China Academy of Traditional Chinese Medicine, Beijing, P.R. China* 

Xiaohua Pei *The Third Affiliated Hospital of Beijing University of Traditional Chinese Medicine, Beijing, P.R. China* 
