Two common epigenetic regulations are DNA methylation and histone acetylation, which modify DNA and histone interactions within chromatins and account for the increase or decrease in gene expression [1–3]. DNA hypermethylation has been shown to inhibit gene transcription, thus reducing gene expression [4–7]. Methylation and deacetylation have been found to play a key role in malignant disorders . Inhibitors of these processes, such as methyltransferase inhibitors and histone deacetylase (HDAC) inhibitors, are novel anti-cancer agents. Two DNA methyltransferase inhibitors, azacitidine and decitabine, and a histone deacetylase inhibitor, vorinostat, have been licensed for clinical use [9–11]. Phenethyl isothiocyanate (PEITC) belongs to the family of natural isothiocyanates, which are found in a wide variety of cruciferous vegetables, and are released when the vegetables are cut or masticated. PEITC has been proven to be an effective HDAC inhibitor, and is able to induce growth arrest and apoptosis in cancer cells both in vitro and in vivo [12–15].
Breast cancer is the most commonly diagnosed cancer among women, accounting for more than 1 in 4 cancers . After lung cancer, breast cancer is the leading cause of cancer death in women. Chemotherapy is a mainstay in breast cancer therapy. New agents are being actively sought [17–21]. Paclitaxel (taxol) is a widely used chemotherapy drug in the treatment of breast cancer , lung cancer , and ovarian cancer . It was first discovered in 1967 , entered clinical trials in 1984 [26–28], and has been a leading chemotherapeutic agent ever since [23, 26, 27, 29]. The mechanism of action of paclitaxel involves its interference with microtubule assembly . Paclitaxel prevents the disassembly of microtubules during mitosis . When taxol binds to tubulin, the microtubules become locked in polymerized state, and thus the cells are restricted from G2 to M phase transition [32–35]. The end result is that the cells are not able to replicate. Another effect of taxol is that it inhibits the anti-apoptosis protein Bcl-2, and induces apoptosis in cancer cells . However, paclitaxel, like most other chemotherapy drugs, has a high level of toxicity as well as a multitude of side effects. The consequence of the toxicity of taxol at a higher dosage is neuropathy which limits its use in patients [23, 26, 27]. Furthermore, cancer cells develop resistance to taxol after prolonged use.
It has been shown in this laboratory that PEITC is a HDAC inhibitor and can suppress HDAC enzyme activity and decrease HDAC enzyme expression in prostate cancer, leukemia, and myeloma cells [12–14, 37–40]. An interesting is that some isothionates have minimal toxicity to normal cells . This project aimed to study the combined effect of PEITC and taxol on breast cancer.