Evaluation of curcumin acetates and amino acid conjugates as proteasome inhibitors

Abstract

Abstract. Curcumin (diferuloylmethane) is the main active ingredient of turmeric, a traditional herbal medicine and food of south Asia. Curcumin has been found to have a wide range of biological activities, including antioxidant, anti-inflammatory, chemopreventive and chemotherapeutic activities. Curcumin is currently being tested in clinical trials for treatment of various types of cancers, including multiple myeloma, pancreatic cancer and colon cancer. Although no toxicity associated with curcumin (even at very high doses) has been observed, the effects of curcumin in other solid tumors have been modest, primarily due to poor water solubility and poor bioavailability in tissues remote from the gastrointestinal tract. Therefore, there is a need for the discovery of curcumin analogs with better water solubility or greater bioavailability for the treatment of solid tumors such as prostate cancer. In this study, curcumin acetates and amino acid conjugates of curcumin were studied in terms of their proteasome inhibitory and antiproliferative effects against several human cancer cell lines. It was found that the water soluble amino acid conjugates of curcumin showed a potent antiproliferative effect and are potent proteasome inhibitors. Docking studies of the curcumin amino acid conjugates for proteasome inhibition were carried out to explain their biological activities. It is suggested that they may serve as the water soluble analogs of curcumin.

Sensitizing human multiple myeloma cells to the proteasome inhibitor bortezomib by novel curcumin analogs

“…Although curcumin is very effective, it is poorly water soluble and less bioavailable in tissues remote from the gastrointestinal tract. In our efforts to enhance its bioavailability we synthesized amino acid-conjugated curcumin analogs and have previously reported them to be potent inhibitors of the proteasome and cell proliferation ( 15 ). Based on our previous work with curcumin analogs we further investigated the efficacy of these analogs as chemosensitizers, in combination with bortezomib.…”

“…Unfortunately, the in vivo biological activities of curcumin were found to be greatly reduced due to its low solubility and bioavailability in tissues remote from the gastrointestinal tract ( 10 – 12 ). In an effort to enhance the bioavailability of curcumin, we synthesized several novel analogs of curcumin, and we recently reported that water soluble amino acid conjugates of curcumin are potent proteasome inhibitors and showed a potent antiproliferative effect in several human cancer cell lines ( 15 ). Docking studies of these conjugates suggested that they may serve as the water soluble analogs of curcumin ( 15 ).…”

“…In an effort to enhance the bioavailability of curcumin, we synthesized several novel analogs of curcumin, and we recently reported that water soluble amino acid conjugates of curcumin are potent proteasome inhibitors and showed a potent antiproliferative effect in several human cancer cell lines ( 15 ). Docking studies of these conjugates suggested that they may serve as the water soluble analogs of curcumin ( 15 ). In the present study, we examined the ability of the curcumin analogs 6–13 ( Fig.…”

“…In the present study, we examined the ability of the curcumin analogs 6–13 ( Fig. 1 ) ( 15 ) to sensitize multiple myeloma cells to otherwise sublethal concentrations of bortezomib and enhance its proteasome-inhibitory anticancer activities.…”

Targeting multiple myeloma with natural polyphenols

“…Despite documented ability of curcumin to inhibit P-glycoprotein, multidrug resistance protein 1, cytochrome P450 monooxygenases, uridine dinucleotide phosphate glucuronosyltransferases and glutathione-stransferase may rise some concerns about curcumin safety in combination with multiple drug regimens. Pharmacokinetic effects exerted by curcumin can produce a reduction in conventional drug doses to obtain measurable therapeutic effects, reducing the entity of side effects and adverse events [22,34] One of the most frustrating inconvenience related to curcumin administration depends on its modest absorption, its rapid metabolism/elimination and thus its poor availability after ingestion [16,21,22,35,36]. An extended panel of solution have been described to overcome the problem of curcumin low bioavailability, ranging from incorporation of curcumin in micelles to the synthesis of analogues with improved bioavailability and superior growth suppressive abilities against aPCs [35 -40].…”