Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
ReviewMechanistic perspectives on cancer chemoprevention/chemotherapeutic effects of thymoquinone
Introduction
Despite a remarkable progress in developing anticancer therapies, the incidence of various cancers and the number of cancer-related deaths are still on the rise [1]. The increasing trend in chemotherapy failure, recurrence of certain tumors after primary cure, and the deterioration of patient's quality of life limit the real success of chemotherapy in fighting cancer [2]. The gain-of-function mutations of cellular proto-oncogenes and the loss-of-function mutations of tumor suppressor genes lead to the neoplastic transformation of cells. Persistent oxidative stress and chronic inflammation play critical roles in the activation of various oncogenes and inactivation of tumor suppressor genes, thereby serving as the pathological basis of carcinogenesis. Reactive oxygen species (ROS) and a wide array of inflammatory mediators not only cause DNA damage but also perturb intracellular signaling network and instigate epigenetic alterations throughout the course of tumor development. A wide variety of plant constituents (phytochemicals with structurally diverse classes of compounds, such as flavonoids, terpenoids, alkaloids, and saponins, etc.) are known to possess antioxidant and anti-inflammatory properties. That some of these chemopreventive phytochemicals possess the ability to sensitize multidrug-resistant cancer cells to undergo apoptosis and block the tumor angiogenesis and metastasis [3], [4], [5], [6] has continued to fuel the search for novel anticancer therapies from edible or non-edible plant sources.
Thymoquinone (2-methyl-5-isopropyl-1,4-benzoquinone; TQ) is a monoterpene present in the seed oil of the plant Nigella sativa L. (family Renunculaceae), commonly known as black cumin or black seed that is widely consumed as a condiment in many societies [7]. The plant has long been used in Ayurvedic medicine for the treatment of various human ailments including gastrointestinal diseases, asthma, obesity, and hypertension. Since the first isolation of TQ from black seed in 1963 by El-Dakhakhany [8], studies have reported diverse pharmacological activities of TQ in support of its folkloric use. The report of the cytotoxic effects of TQ in human cancer cells [9] and that on human tumor cell lines resistant to doxorubicin and etoposide [10], cemented the interest in TQ as a potential chemopreventive agent. This review highlights the essence of the molecular targets of TQ in the prevention and treatment of cancer.
Section snippets
Cancer chemoprevention and chemotherapeutic potential of TQ: evidence from in vivo studies
A large number of animal model studies have demonstrated that TQ inhibited experimentally induced carcinogenesis in the colon, forestomach, oral cavity, liver and skin, and retarded the growth of cancer cell xenograft tumors in vivo. The current knowledge base is documented in Table 1. The administration of TQ in drinking water significantly reduces the incidence and the multiplicity of forestomach tumors [11] and the development of fibrosarcoma [12] in Swiss albino mice treated with
Biochemical basis of anticancer effects of TQ
Mechanistically, TQ has been shown to inhibit various hallmarks of cancer. Major mechanisms of its anticancer effects include: inhibition of carcinogen activation, inflammation and tumor cell proliferation, activation of antioxidant and/or detoxification enzymes, induction of cancer cell death, and suppression of tumor angiogenesis, invasion and metastasis (Fig. 1) [25]. The biochemical mechanisms and potential molecular targets of TQ are summarized in Table 2.
Upstream kinases and transcription factors as molecular targets of TQ
Dysregulation of intracellular signaling pathways comprising various kinases and transcription factors help tumor cells to acquire the various hallmarks of cancer. The modulation of aforementioned biochemical processes by TQ results from its ability to interfere with deregulated cell signaling pathways. The components of cell signaling network, hence, appear as major molecular targets of TQ.
Safety and clinical relevance
Badary and colleagues [116] have reported that the LD50 value of TQ in mice was 2.4 g/kg after acute oral administration and the compound was well tolerated when given at a dose of 90 mg/kg/d for 90 days [116]. Oral administration of a TQ-rich nano-emulsion to rats for 14 days also did not produce any signs of toxicity [117]. In a phase I clinical study comprising twenty-one patients with solid tumors and hematological cancers, treatment with TQ showed slight improvement in general conditions and
Concluding remarks
There is now growing interest in searching anticancer phytochemicals with multi-targeted mechanisms of action, because intervening with a particular oncogenic signaling pathway may help tumor cell to activate alternative survival pathways for promotion and progression of cancer. As has been discussed above, TQ targets diverse biochemical processes to elicit anticancer activities. Based on the chemopreventive and/or chemotherapeutic potential of TQ, attempt has been made to synthesize various
Conflict of interests
Authors declare that no conflict of interest exists.
Acknowledgement
This work has been supported by the Settlement Research Grant-2012-0195 of Keimyung University allocated to Joydeb Kumar Kundu.
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Combinatorial effect of thymoquinone with chemo agents for tumor therapy
2022, PhytomedicineCitation Excerpt :This triple combination therapy also significantly reduced tumor size in the HuT-102 xenograft model of mice (Houssein et al., 2020). As a folk-derived medicine TQ exhibits both chemotherapeutic and chemopreventive activities (Kundu et al., 2014). Several in vivo studies have shown that TQ reduced the chemotoxic effects of chemo agents to vital organs, including liver, heart, kidneys and lungs (Table 2).
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These authors contributed equally to this work.