Efficacy of Selected Natural Products as Therapeutic Agents against Cancer

Abstract

With emerging sophistication in the exploration of ocean environment, a number of marine bioactive products have been identified with promising anticancer activity. Many of these are in active phase I or phase II clinical trials or have been terminated because of adverse side effects, mainly hematological in nature. Nonetheless, the information derived has aided enormously in providing leads for laboratory synthesis with modifications in the parent structure affecting compound solubility, absorption, and toxicity, resulting in less severe toxicity while achieving maximum efficacy in smaller doses. We describe herein, a few of the compounds obtained from marine and terrestrial sources [bryostatin 1 ( 1), dolastatin 10 ( 2), auristatin PE ( 3), and combretastatin A4 ( 4)] that have been extensively investigated in our laboratory and continue to be investigated for their sensitization effects with other cytotoxic agents in several different site-specific tumors employing murine models or human subjects.

Identification of the Human UDP-Glucuronosyltransferases Involved in the Glucuronidation of Combretastatin A-4

“…CA-4 prodrug phosphate, which was intravenously administered by brief infusion, completed phase I clinical trials and four studies have been published showing that CA-4 was safe, well tolerated, and lacking in hematological toxicity. A marked reduction of blood flow in a variety of tumors at doses lower than the maximum tolerated dose was also observed (Banerjee et al, 2008). In these studies, it has also been stated (Dowlati et al, 2002;Rustin et al, 2003) that the formation of glucuronide is the main metabolic pathway that contributes to the clearance of CA-4.…”

“…Combretastatin A-4 is a new, promising anticancer drug at present undergoing clinical study (Banerjee et al, 2008). The formation of a related glucuronide as the major CA-4 metabolite was demonstrated (Aprile et al, 2009) in rat and human liver fractions as well as in vivo in rat.…”

Marine natural products: Bryostatins in preclinical and clinical studies

“…It was originally isolated from the marine organism Bugula neritina L. (Bugulidae), often found in the form of moss-like colonies attached as a foulant to dock sides, pilings, buoys floats and vessel hulls, or occurring on rocks and shells (Banerjee et al, 2008). Only multigram quantities of highly pure bryostatin-1 were obtained from about 10 000 gallons (45 500 L) of Bugula neritina (Schaufelberger et al, 1991).…”

“…To date, phase II studies of bryostatin-1 have failed to demonstrate any clinically meaningful activity. Despite the lack of significant clinical benefit observed when used as a single agent, additional upcoming results revealed synergistic action between bryostatin-1 and conventional cytotoxic drugs, which triggered several phase I studies of bryostatin in combination with cytotoxic agents (Banerjee et al, 2008). These include cisplatin, vinca alkaloids (vincristine), paclitaxel, nucleosides (fludarabine, gemcitabine), cytokines (interleukin-2, GM-CSF), or protein kinase inhibitor temsirolimus (Newman, 2012).…”

Marine bioactive products as anti-cancer agents: effects of sea anemone venom on breast and lung cancer cells

“…Many of these natural compounds in are venom used to acquire prey and as chemical defence against predators in nature [1] . Numerous toxic peptides are found within these venoms, and some of them have been used to investigate biomedical problems including designing novel drugs [2] .…”