Lipophilic Caffeic and Ferulic Acid Derivatives Presenting Cytotoxicity against Human Breast Cancer Cells

Abstract

In the present work, lipophilic caffeic and ferulic acid derivatives were synthesized, and their cytotoxicity on cultured breast cancer cells was compared. A total of six compounds were initially evaluated: caffeic acid (CA), hexyl caffeate (HC), caffeoylhexylamide (HCA), ferulic acid (FA), hexyl ferulate (HF), and feruloylhexylamide (HFA). Cell proliferation, cell cycle progression, and apoptotic signaling were investigated in three human breast cancer cell lines, including estrogen-sensitive (MCF-7) and insensitive (MDA-MB-231 and HS578T). Furthermore, direct mitochondrial effects of parent and modified compounds were investigated by using isolated liver mitochondria. The results indicated that although the parent compounds presented no cytotoxicity, the new compounds inhibited cell proliferation and induced cell cycle alterations and cell death, with a predominant effect on MCF-7 cells. Interestingly, cell cyle data indicates that effects on nontumor BJ fibroblasts were predominantly cytostatic and not cytotoxic. The parent compounds and derivatives also promoted direct alterations on hepatic mitochondrial bioenergetics, although the most unexpected and never before reported one was that FA induces the mitochondrial permeability transition. The results show that the new caffeic and ferulic acid lipophilic derivatives show increased cytotoxicity toward human breast cancer cell lines, although the magnitude and type of effects appear to be dependent on the cell type. Mitochondrial data had no direct correspondence with effects on intact cells suggesting that this organelle may not be a critical component of the cellular effects observed. The data provide a rational approach to the design of effective cytotoxic lipophilic hydroxycinnamic derivatives that in the future could be profitably applied for chemopreventive and/or chemotherapeutic purposes.

The Molecular Basis for the Pharmacokinetics and Pharmacodynamics of Curcumin and Its Metabolites in Relation to Cancer

“…At the administered dosages, ferulic acid was not carcinogenic (Kaul and Khanduja, 1998;Balakrishnan et al, 2008;Alias et al, 2009;Baskaran et al, 2010). Moreover, in human breast cancer (T47D) cells, ferulic acid inhibited proliferation at an IC 50 of 2.3 nM (Kampa et al, 2004), although inhibition of cell proliferation and apoptosis could not be reproduced in other human breast cancer cell lines at ferulic acid concentrations of up to 75 mM (Serafim et al, 2011). At concentrations of 150-1500 mM, however, ferulic acid was able to reduce cell viability in cultured rat hepatoma (HTC) cells (Maistro et al, 2011).…”

Cytotoxic Effects of Phytophenolics from Caesalpinia mimosoides Lamk on Cervical Carcinoma Cell Lines through an Apoptotic Pathway

“…Vanillic acid, a vegetable phenolic compound, is a strong antioxidant (Erdem et al, 2012). Moreover, ferulic acid enhances radiation effects by increasing lipid peroxidative markers in two cervical cancer cell lines, namely HeLa and ME-180, in vitro (Karthikeyan et al, 2011;Serafim et al, 2011). An in vivo model has shown that resveratrol has not only anti-inflammatory, anti-oxidant, anti-mutation, anti-proliferation and anticell cycle activities but also induces apoptosis and has synergistic effects with chemotherapeutic drugs (Frampton et al, 2010;Hahnvajanawong et al, 2011).…”

“…Plant phytochemicals have been reported to prevent a number of diseases, including cancer, cardiovascular disease, infection and inflammation. In vitro studies have revealed that some phytochemicals, such as gallic acid (Gali et al, 1991;Ohno et al, 2001;Kim 2007;You et al, 2010;Lu et al, 2010), caffeine (Kawano et al, 2012), vanillic acid (Erdem et al, 2012), and ferulic acid (Karthikeyan et al, 2011;Serafim et al, 2011), are cytotoxic to cell lines. An in vivo model has shown that resveratrol not only has anti-inflammatory, anti-oxidative, anti-mutation, anti-proliferative, and anti-cell cycle properties but also induces apoptosis and has synergistic effects with chemotherapeutic drugs (Frampton et al, 2010;Hahnvajanawong et al, 2011).…”

Naturally Occurring Substances and Their Role in Chemo-protective Effects

“…The main sources of ferulic acid are foods such as wheat bran, but also coffee, apples, artichokes, peanuts, oranges, and pineapples. Animal studies and in vitro studies suggest that ferulic acid may have direct antitumour activity against breast and colon cancer (53)(54)(55). Ferulic acid has a significant role in the inhibition of abnormal cell proliferation in cancer cells occurring in induced carcinogenesis due to its modulatory effect on pro-apoptotic genes p53 and bcl-2 expression (56).…”