ReviewFoundationThymoquinone: fifty years of success in the battle against cancer models
Introduction
Thymoquinone (TQ) has been chemically synthesized for years by oxidation of thymol with hydrogen peroxide. This year marks the 50th anniversary of TQ's first isolation from a natural product when in 1963 it was identified in the essential oil of the Nigella sativa L. black seed, one of the most used plants in folk medicine in the Mediterranean region and West Asia [1]. Later, TQ was isolated from other plants with therapeutic properties namely Eupatorium ayapana [2], the leaves of several Origanum species [3], the heartwood essential oils of Calocedrus decurrens [4], the oil of different Satureja species [5], the aerial flowering parts of Thymus vulgaris L. [6] and from Nepeta distans Raul [7].
Nigella sativa commonly known in the Middle East as Habbatul Baraka or the ‘seed of blessing’ has curative potential as described in the Old Testament and by the prophet4 himself [1]. Black seed oil is traditionally used for enhancing immunity and combating inflammatory and respiratory diseases, among many disorders. Scientific research supports the folk medicine use of the oil as an antiinflammatory, antimicrobial, and antidiabetic agent [1].
Both TQ and its carbonyl polymer Nigellone have been mainly investigated for their anti-inflammatory and anticancer activities. For 10 years, we have studied the anticancer effects of TQ and provided evidence for its promise both in vitro and in vivo. What makes TQ interesting is that it is readily available from a plant source and is not toxic to normal tissues. Rather, TQ protects many organs from standard chemotherapy-induced damage, and enhances the efficacy of chemotherapeutic agents even in resistant cancers [1].
Nigella sativa and TQ's anti-inflammatory potential account for the observed analgesic, antidiabetic, and antihistaminic effects, and ability to alleviate respiratory diseases, rheumatoid arthritis, multiple sclerosis, and Parkinson's disease [8]. Three patents have been filed on behalf of TQ for the treatment of cancer, sepsis syndrome and urinary tract infections. The first was filed in 1999 for the treatment of parental and multi-drug resistant (MDR) human cancers (US 6218434 B1). Ten years later, a patent was filed for the treatment and prevention of sepsis syndrome (US 20100273893 A1) and a formulation containing TQ was patented for treating urinary tract inflammatory conditions in the following year (United States Patent Application: 20100028468). Moreover, TQ has demonstrated great potential against many microbes and parasites [8] and was shown to prevent atherosclerosis, osteoporosis, hypertension, and epilepsy 9, 10. A recent clinical study in children further supports TQ's antiepileptic role [11].
As of May 2013, the term “thymoquinone” brings up 345 search results in the Pubmed database. The first paper describing TQ's anticancer activity was published 35 years after its isolation. Approximately 70% of the papers on TQ appeared in the past five years, one-third of which describe its anticancer properties. This reflects increased recent interest in TQ's therapeutic properties, and underscores the necessity for reviewing its anticancer activities. For this reason, we sought to revisit the grounds which made TQ the promising anticancer agent it is today by emphasizing its effects on the universal cancer hallmarks and the underlying signaling mechanisms.
Section snippets
TQ isolation and chemical characterization
The yellow crystalline molecule TQ (2-methyl-5-isopropyl-1,4-benzoquinone) was isolated using thin layer chromatography on silica gel [12]. TQ has a basic quinone structure consisting of a para substituted dione conjugated to a benzene ring to which a methyl and an isopropyl side chain groups are added in positions 2 and 5, respectively (Fig. 1). The crystal structure of TQ was later determined by high-resolution X-ray powder diffraction [1]. For quantifying TQ, several methods including
Pharmacological properties of TQ
TQ was found to exert its biological functions by modulating the physiological and biochemical processes involved in ROS generation. In normal tissues, TQ acts as a strong antioxidant and inhibits the production of superoxide radicals and lipid peroxidation, or increases the activities of the antioxidant enzymes superoxide dismutase (SOD), catalase, glutathione (GSH), glutathinone transferase and quinone reductases 9, 10, 14, 15. In tumors, however, TQ induces ROS generation 16, 17 and
TQ analogs and nanoparticle formulations
Hydrophobic drugs commonly show poor bioavailability when given to animals due to their low absorption capacity, which results in low amounts of drug reaching the target tumor and increased toxicity to normal tissues. Considering that TQ is a hydrophobic molecule, many laboratories have attempted to synthesize more soluble TQ analogs and to encapsulate it in nanoformulations.
Two different studies have conjugated TQ with fatty acids to enhance its membrane penetration capacity and antitumor
Modulation of cancer hallmarks by TQ
Cancer development is a progressive multistep process during which normal cells acquire traits that enable their transformation into malignant tumors. These traits, also called the hallmarks of cancer were described by Hanahan and Weinberg in 2000 and subsequently revised by them in 2011 [34].
The ten cancer hallmarks [34] are common to most tumors. Drugs which interfere with one or more of these hallmarks are considered promising anticancer therapeutics, with some even making it to the clinic.
In vivo toxicity and anticancer activity of TQ
TQ toxicity has been assessed in several animal models in addition to a Phase I clinical trial 79, 80. Only one study investigated the efficacy of TQ in adult patients with solid tumors or hematological malignancies who had failed or relapsed from standard therapy [80]. In animal models, the histopathological analysis of liver, kidney, heart and lungs of mice and rats given TQ enabled the determination of nontoxic doses [79]. In mice, TQ's LD50 following oral and intraperitoneal administration
Adjuvant potential of TQ
Combination therapies are being increasingly employed in the battle against cancer, particularly against resistant tumors. It would be ideal to combine the toxic chemotherapeutic drugs with non-toxic natural drugs for greater efficacy and fewer unpleasant side effects. TQ has been used in combination with hormones, chemotherapeutic agents, and with ionizing radiation. Extensive evidence from in vitro and in vivo studies indicates that TQ improves the therapeutic efficacy of many
Limitations of clinical translation of TQ
The main limitations for translating TQ to the clinic is its poor bioavailability, in addition to the lack of knowledge about its toxicity in humans and the lack of understanding of its exact molecular targets. Systems and network biology studies can help determine the potential molecular targets of TQ, as well as understand the mechanisms by which they are regulated. Several programs and servers can be used for identifying potential binding partners, and virtually visualizing candidate sites
Concluding remarks
TQ is a natural product that can be used for the treatment of a wide number of diseases. Over the past five years, there has been a significant increase in research on TQ, particularly describing its anticancer effects. The attractive feature of TQ is that it is not only able to selectively target tumor cells, but it can also protect normal tissues from the toxic side effects of chemotherapeutic agents when used as an adjuvant. The mechanism of anticancer action of TQ involves differential
Acknowledgements
The authors would like to acknowledge the University of Erlangen, Germany, the Deutsche Forschungsgemeinschaft and the American University of Beirut, Lebanon for their continued support. Mr. Bassel Bou Dargham and Ms. Danielle Fayad helped with the literature review and preparation of figures.
Regine Schneider-Stock is Professor of Experimental Tumorpathology at the Friedrich-Alexander-University Erlangen-Nürnberg. She earned her PhD from the Institute of Neuroscience and Brain Research at the Academy of Sciences, Magdeburg, Germany, in 1991. Her main research interests are epigenetics and cell death mechanisms in colorectal cancer.
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Cited by (0)
Regine Schneider-Stock is Professor of Experimental Tumorpathology at the Friedrich-Alexander-University Erlangen-Nürnberg. She earned her PhD from the Institute of Neuroscience and Brain Research at the Academy of Sciences, Magdeburg, Germany, in 1991. Her main research interests are epigenetics and cell death mechanisms in colorectal cancer.
Isabelle H. Fakhoury is a PhD candidate in Cell and Molecular Biology at the American University of Beirut. She earned her Master's degree from the Paris Diderot University, Paris. Her research currently focuses on thymoquinone nanoparticles formulation.
Angela M. Zaki is at present a graduate student in Clinical Laboratory Sciences at Georgia Regents University, USA. She was formerly a graduate student at the American University of Beirut, Lebanon. She earned her Bachelors degree in Biology from the Lebanese University, Lebanon.
Chirine O. El-Baba is a PhD candidate at the faculty of natural sciences in Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Germany. In 2009, she earned her Master's degree in genetics from the University of Pierre and Marie Curie, in Paris, France. Her PhD work focuses on thymoquinone modality and function in combination therapies.
Hala U. Gali-Muhtasib is Professor of Biology at the American University of Beirut. She earned her PhD from Kansas State University, USA, in 1990. Her main research interests are to identify cell death mechanisms of cancer chemopreventive and chemotherapeutic compounds derived from plants.
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Equally contributed to the work.