**4. Conclusion**

Curcumin has a great potential in cancer therapy and is gaining wide acceptance as a preventive treatment agent due to its safety. It affects multiple steps in the carcinogenic process, which is important in avoiding chemoresistance. Clinical studies have indicated its efficacy as a single agent or in combination therapy; however, more rigorous testing are needed. Furthermore, problems associated with the low bioavailability of curcumin, including poor absorption, rapid metabolism, and limited tissue distribution, must be addressed. Current strategies that have been investigated to overcome these problems include alternative administration routes, chemical modifications, and various drug delivery and formulation strategies. These strategies will likely benefit the development of curcumin as an anticancer agent.

### **5. Acknowledgment**

This work was supported by NIH grants R01-HL076340, R01-HL076340-04S1, and R01- HL095579.

### **6. References**

358 Advances in Cancer Therapy

dose-limiting toxic effect in healthy volunteers, not even minor adverse effects such as

Expanding from the above findings, another phase I clinical study was conducted in patients with colon adenocarcinoma to investigate the phamacodynamic of curcumin (Sharma et al., 2004). Curcuminoid, formulated as 500 mg in soft gelatin capsule containing 450 mg of curcumin, 40 mg of desmethoxycurcumin, and 10 mg of bisdesmethoxycurcumin, was taken orally at the dose of 450, 900, 1800, and 3600 mg/day of curcumin for 4 months. Since curcumin is known to induce glutathione S-transferase (GST), suppress prostaglandin E2 (PGE2) production, and inhibit oxidative DNA adduct (M1G) formation, these biomarkers are frequently used to indicate curcumin efficacy. Curcumin and its metabolites were collected from plasma, urine, and feces, and analyzed to assess the pharmacokinetic parameters. The results showed that curcumin was well tolerated by the patients without a dose-limiting toxicity, except in a few cases where patients reported a minor gastrointestinal upset. The result also showed that curcumin at the dose of 3600 mg/day was suitable for phase II evaluation. Curcumin was shown to inhibit PGE2 without affecting GST and M1G, suggesting that GST and M1G may not be useful as indicators for curcumin efficacy. Furthermore, curcumin and its glucuronide and sulfate metabolites were found in the plasma and urine. The presence of these metabolites at all time points indicates that

Consistent with the above finding, numerous other studies have demonstrated low systemic bioavailability of curcumin resulting from poor absorption, rapid metabolism, and rapid systemic elimination (Hsu et al., 2007; Ireson et al., 2001; Maiti et al., 2007; Garcea et al., 2004). Glucuronide and sulfate metabolites of curcumin are rapidly detected in the peripheral and portal circulation after curcumin administration (Garcea et al., 2004). In this study, patients with liver metastasis from colorectal adenocarcinoma were administered orally with curcumin at the daily dose of 450, 1800, and 3600 mg for a week. No curcumin or its metabolites was detected in the bile or hepatic tissue, indicating that curcumin is not

In a phase II clinical study conducted in patients with advanced pancreatic cancer, curcumin was administered orally at the dose of 8 g/day for 8 weeks (Dhillon et al., 2008). The treatment was well tolerated by the patients with no systemic side effects, while effectively reducing the tumor size and the activation of NF-B and COX-2. Mechanistically, curcumin induces cancer cell apoptosis through an upregulation of p53 in the tumor tissues (He et al.,

Curcumin has a great potential in cancer therapy and is gaining wide acceptance as a preventive treatment agent due to its safety. It affects multiple steps in the carcinogenic process, which is important in avoiding chemoresistance. Clinical studies have indicated its efficacy as a single agent or in combination therapy; however, more rigorous testing are needed. Furthermore, problems associated with the low bioavailability of curcumin, including poor absorption, rapid metabolism, and limited tissue distribution, must be addressed. Current strategies that have been investigated to overcome these problems include alternative administration routes, chemical modifications, and various drug delivery and formulation strategies. These strategies will likely benefit the development of curcumin

curcumin has poor systemic availability when given orally.

suitable for treating patients with tumors distant from the absorption site.

diarrhea (Lao et al., 2006).

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**4. Conclusion** 

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**17**

*Lebanon* 

**Salograviolide A: A Plant-Derived** 

Isabelle Fakhoury and Hala Gali-Muhtasib

*American University of Beirut* 

**Sesquiterpene Lactone with Promising**

**Anti-Inflammatory and Anticancer Effects** 

Natural products are chemical substances produced by living organisms of the Biota superdomain, namely plants, animals, fungi and bacteria (G. & C. Merriam Co., 1913). Up to 80% of all drugs discovered prior to 1981 and 50% of all approved drugs between the years 1994 and 2007 are of natural product origin (Harvey, 2008). The contribution of natural products derived from plants, particularly to the well-being of mankind, extends very far back in history. Some of the most famous findings supportive of this fact come from the Middle East region and include documented medical papyri of ancient Egyptians dating back to ca. 1,850 B.C., as well as recent studies revealing their use of medicinal herbs dispensed in grape wine ca. 3,150 B.C. (McGovern et al., 2009). Incidentally, the oldest evidence for the use of herbal medicine to be so far discovered dates back to the prehistoric Neanderthal man who

Several world heritages of medicinal plants have also inspired and greatly contributed to the development of modern medicine (Azaizeh et al., 2008). Indeed some of the early drugs were derived from plants. Morphine, for instance, was the first pharmacologically active pure compound to be extracted from a plant over 200 years ago (Jesse et al., 2009). Clinical, pharmacological, and chemical studies have since then led to the identification of a lengthy list of drugs derived from plants covering a wide range of diseases from diabetes, malaria,

The story of the discovery of plants exhibiting anticancer properties in particular, began almost fifty years ago. With the increase in cancer incidences, there has been an increase of interest in screening for anti-tumor agents from diverse sources including plants. For that purpose, in 1960 the National Cancer Institute (NCI) launched a large-scale screening of 35,000 sample plants. The program resulted among others, in the discovery in 1967 of the best-selling anticancer drug today; Taxol (Cragg, 1998). This breakthrough boosted cancer researchers all over the world and especially those in regions with high diversity to explore the indigenous plants' active ingredients efficacy against cancer. Considering that more than 60% of anticancer drugs available for clinical use today are derived from natural products including plants (Balunas et al., 2005; Newman and Cragg, 2007), one cannot deny that there has been a successful contribution of plants to the fight against cancer (reviewed in Gali-

lived also in the Middle East region around 60,000 years ago (Solecki, 1971).

microbial infections, osteoporosis to inflammation and cancer.

Muhtasib and Bakkar, 2002; Darwiche et al., 2007).

**1. Introduction** 

amyloid in vivo. *Journal of Biological Chemistry*, Vol. 280, No. 7, (December 2004), pp. 5892-5901, ISSN 1083-351X

