Safe and targeted anticancer therapy for ovarian cancer using a novel class of curcumin analogs

Abstract

A diagnosis of advanced ovarian cancer is the beginning of a long and arduous journey for a patient. Worldwide, approximately half of the individuals undergoing therapy for advanced cancer will succumb to the disease, or consequences of treatment. Well-known and widely-used chemotherapeutic agents such as cisplatin, paclitaxel, 5-fluorouracil, and doxorubicin are toxic to both cancer and non-cancerous cells, and have debilitating side effects Therefore, development of new targeted anticancer therapies that can selectively kill cancer cells while sparing the surrounding healthy tissues is essential to develop more effective therapies. We have developed a new class of synthetic curcumin analogs, diarylidenyl-piperidones (DAPs), which have higher anticancer activity and enhanced bio-absorption than curcumin. The DAP backbone structure exhibits cytotoxic (anticancer) activity, whereas the N-hydroxypyrroline (-NOH) moiety found on some variants functions as a cellular- or tissue-specific modulator (antioxidant) of cytotoxicity. The anticancer activity of the DAPs has been evaluated using a number of ovarian cancer cell lines, and the safety has been evaluated in a number of non-cancerous cell lines. Both variations of the DAP compounds showed similar levels of cell death in ovarian cancer cells, however the compounds with the -NOH modification were less toxic to non-cancerous cells. The selective cytotoxicity of the DAP-NOH compounds suggests that they will be useful as safe and effective anticancer agents. This article reviews some of the key findings of our work with the DAP compounds, and compares this to some of the targeted therapies currently used in ovarian cancer therapy.

Figure 1

Structures of curcumin, EF24 (3,5-bis(2-flurobenzylidene piperidin-4-one) and DAP compounds are shown. DAP-F(p) and DAP-CF3(p) are 3,5-diarylidenyl piperidones containing para-fluoro substitutions on the phenyl groups. DAP-F(p)-NOH and DAP-CF3(p)-NOH contain an N-hydroxy-pyrroline moiety covalently linked to the N-terminus of the piperidone ring. (DAP figures reproduced with permission from Free Radical Biology and Medicine/Elsevier, reference # 46).

Figure 2

The dual functionality of DAP-F(p)-NOH or DAP-CF3(p)-NOH compounds. The reductive environment of the cancer cells shifts the equilibrium balance, such that less antioxidant cytoprotection is afforded to cancer cells versus normal cells. The –NOH (N-hydroxy-pyrroline) moiety undergoes conversion to and exists in equilibrium with the nitroxide (>NO) form (shown in the circle).