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Despite great advances, therapeutic approaches of osteosarcoma, the most prevalent class of preliminary pediatric bone tumors, as well as bone-related malignancies, continue to demonstrate insufficient adequacy. In recent years, a growing trend toward applying natural bioactive compounds, particularly phytochemicals, as novel agents for cancer trea...
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... to the cell production and increased cell proliferation may lead to cancer [82]. In the highly elaborate process of the cell cycle, a mother cell produces two daughter cells. Thus, controlling the cell cycle and proliferation is one of the suggested ways of inhibiting cancer development [83]. Different phases of the cell cycle are presented in Fig. 3. Briefly, most cells in the mature animals are found in the stable state and at the G 0 (gap) phase of the cell cycle. When dividing, cells can launch the G 1 phase. In the majority of cells, DNA replication occurs within a narrow part of the cell cycle known as the S (synthesis) phase. Following the S phase, the cell initiates the ...
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Nonylphenol (NP), a well-known endocrine-disrupter chemical, has several harmful effects on the central nervous system including neuroendocrine disruption, cognitive impairment, and neurotoxicity. Thymoquinone (TQ) is a main bioactive compound in the black seeds of Nigella sativa that has antioxidant, anti-inflammatory, and neuroprotective properti...
Citations
... Once bone metastasis arises, the patient survival rate drops to less than 30% [4], usually triggering several bone-related clinical manifestations such as bone pain, pathological fracture, and nerve compression syndrome that often lead to a poor prognosis for prostate cancer patients [5]. Osteosarcoma (OS) is known as the most prevalent and aggressive malignant bone disease, with a worldwide incidence of about one to three cases per million per year [6]. In addition, patients with metastatic osteosarcoma exhibit unsatisfactory responses to currently available chemotherapeutics. ...
In the present work, we successfully synthesized Se-alkyl selenopyridines 1 and 3, selenopheno[2,3-b]pyridine 2, and bis-selenopyridine 4 derivatives using an eco-friendly method by utilizing NaHSe instead of toxic hydrogen selenide. The effect of the temperature on the reaction was screening at various temperatures. The regiospecific reaction of selenopyridine 1 with bromine afforded an unexpected product 4,6-diamino-5-bromo-2-[(cyanomethyl)selenyl]-pyridine-3-carbonitrile (5), which was cyclized to selenopheno[2,3-b]pyridine (7) by refluxing in the presence of TEA. While its treatment with thiophenol and/or p-chlorothiophenol gave 8a, b. On the other hand, its reaction with aminothiophenol afforded 2-(benzo[d]-thiazol-2-yl)-5-bromoselenopheno[2,3-b]pyridine-3,4,6-triamine (9). Also, N-(2-cyano-4-methyl-5H-1-seleno-3,5,8-triazaacenaphthylen-7-yl)acetamide (11) and a novel series of selenoazo dyes 12a–d were synthesized by treatment of selenopheno[2,3-b]pyridine 2 with acetic anhydride and/or diazonium chlorides of aromatic amines, respectively. Then, we ascertained the potential activity of synthesized compounds against highly metastatic prostate cancer cells (PC-3) and osteosarcoma cells (MG-63) and found that 12a, 12b, 12c, and 12d were more cytotoxic than doxorubicin in both tested cell lines, showing nearly the same anticancer activity with IC50 values ranging from 2.59 ± 0.02 µM to 3.93 ± 0.23 µM. Mechanistically, the most potent compounds 12a and 12b proved to be potent EGFR inhibitors with IC50 values of 0.301 and 0.123 µM, respectively, compared to lapatinib as a positive reference (IC50 = 0.049 µM). Moreover, the docking results are in good agreement with the anticancer activity as well as the EGFR inhibitory activity, suggesting these two compounds as promising EGFR anticancer candidates.
Graphical abstract
... The detrimental/beneficial effects of TQ on healthy intestinal epithelial cells should be studied using similar concentrations. Despite the tumoricidal properties of TQ on different cancer cell types, TQ lacks cytotoxicity in normal cells [43]. One reason would be that TQ can reach to subcellular compartment and regulate the activity of various kinases and transcription factors associated with tumorigenesis [43]. ...
... Despite the tumoricidal properties of TQ on different cancer cell types, TQ lacks cytotoxicity in normal cells [43]. One reason would be that TQ can reach to subcellular compartment and regulate the activity of various kinases and transcription factors associated with tumorigenesis [43]. ...
Colorectal cancer (CRC) is deadly anaplastic changes in the gastrointestinal tract with high-rate mortality. In recent years, the application of phytocompounds has been extended along with different therapeutic protocols. Here, we monitored the effects of Thymoquinone (TQ) on autophagy via mitochondrial function after modulation of the Wnt/β-catenin signaling pathway.
Human colorectal adenocarcinoma HT-29 cells were treated with TQ (60 μM) and 15 μM Wnt3a inhibitor (LGK974) for 48 hours. The survival rate was evaluated using an MTT assay. The expression of Wnt-related factors (c-Myc, and Axin), angiogenesis (VE-Cadherin), and mitophagy-related factors (PINK1, OPTN) was assessed using real-time PCR assay. Protein levels of autophagy factors (Beclin-1, LC3, and P62) were monitored using western blotting. Using flow cytometry analysis, the intracellular accumulation of Rhodamine 123 was evaluated. The migration properties were analyzed using a scratch wound healing assay.
Data indicated that TQ can reduce the viability of HT-29 cells compared to the control cells (p<0.05). The expression of VE-Cadherin was inhibited while the expression of PINK1 was induced in treated cells (p<0.05). Both LGK974 and TQ-treated cells exhibited activation of autophagy flux (Beclin-1↑, LC3II/I↑, and p62↓) compared to the control group (p<0.05). TQ can increase intracellular accumulation of Rhodamine 123, indicating the inhibition of efflux mechanisms in cancer cells. Along with these changes, the migration of cells was also reduced (p<0.05).
TQ is a potential phytocompound to alter the dynamic growth of human colorectal HT-29 cells via the modulation of autophagy, and mitophagy-related mechanisms.
... Lip-TQ-Vit C exhibited the most effective inhibition compared with the other liposomal formulations, on both A549 lung cancer cells and HT29 colorectal cancer cells. This is mainly due to the anticancer effect of TQ, as TQ demonstrates its potency as an effective anticancer compound and positioning it as a promising candidate for small-scale therapeutic intervention in both cancer prevention and management [26][27][28][29]. Fortunately, in this study vitamin C was combined with TQ and showed synergistic activity with combination index (CI <1) ( Figure 6A, B & C). ...
Background: Thymoquinone (TQ) and vitamin C (Vit C) have demonstrated individual anticancer effects in various studies. TQ exhibits inhibitory properties against tumor growth, induces apoptosis, while Vit C protects against DNA damage and oxidative stress. Aim: Formulation of TQ and Vit C combination into liposomes using two methods and investigate the synergistic anticancer. Method: Liposomal preparations were characterized, and the purity of drug components was confirmed using encapsulation efficiency (EE %). Results: In vitro cell viability studies demonstrated the inhibitory effect of TQ and Vit C against colorectal (HT29, 5.5 ± 0.9 μM) and lung cancer (A549, 6.25 ± 0.9 μM) cell lines with combination index <1. Conclusion: The formulation of TQ and Vit C displayed synergistic anticancer activity.
... Studies on the anticancer activities of TQ have revealed that TQ can inhibit cancer cell proliferation and also stimulate apoptosis [7]. Various studies report the anticancer and anti-inflammatory effects of TQ for various cancer types, including breast [12], blood [13], lung [14], pancreatic [15], prostate [16], bone [17], and colorectal cancer [18]. Despite this, a small number of studies have revealed its effects on brain cancer and GBM. ...
Objectives
Glioblastoma is a fast-growing and aggressive brain tumor. Despite the current treatment methods, such as chemical and surgical operations, the prognosis is still poor. Therefore, combined therapeutic strategies are proposed to maximize therapeutic efficacy and reduce toxicity. Thymoquinone has been shown to have neuroprotective effects in addition to its anti-cancer effects on different types of cancer. 5-Fluorouracil, on the other hand, is a cytotoxic chemotherapy agent used to treat cancer. As a synergistic combinational approach, this study aimed to examine the antiproliferative effects and production of reactive oxygen species in a glioblastoma cell line.
Methods
We have tested thymoquinone and 5-fluorouracil alone and in their combination to observe cellular growth with MTT assay. The combinational effects of the agents were determined by the CompuSYN software program. Cell proliferation was assayed with crystal violet assay. Reactive oxygen species production was analyzed by 2′,7′-dichlorodihydrofluorescein diacetate in glioblastoma cells.
Results
Thymoquinone and 5-fluorouracil inhibited cell growth of glioblastoma cells with half maximal inhibitory concentrations (IC 50 ) of 45.93 and 14.02 µM for 48 h, respectively. At synergistic combinational concentrations, the crystal violet assay demonstrated that there is a positive correlation between combination index values and cell proliferation. Also, an increment in the production of reactive oxygen species was observed upon combinational treatments.
Conclusions
Our results indicate that the combinational strategy of these two agents reduced cell viability and proliferation in glioblastoma cells and showed strong synergistic anticancer efficiency.
... TQ is the main bioactive component of the volatile oil of N. sativa [18,[25][26][27]. Other components of N. sativa L. are thymohydroquinone, thymol, carvacrol, nigellidine, nigellicine, and α-hederin [28,29]. ...
Colorectal neoplasms are one of the deadliest diseases among all cancers worldwide. Thymoquinone (TQ) is a natural compound of Nigella sativa that has been used in traditional medicine against a variety of acute/chronic diseases such as asthma, bronchitis, rheumatism, headache, back pain, anorexia, amenorrhea, paralysis, inflammation, mental disability, eczema, obesity, infections, depression, dysentery, hypertension, gastrointestinal, cardiovascular, hepatic, and renal disorders. This review aims to present a detailed report on the studies conducted on the anti-cancer properties of TQ against colorectal cancer, both in vitro and in vivo. TQ stands as a promising natural therapeutic agent that can enhance the efficacy of existing cancer treatments while minimizing the associated adverse effects. The combination of TQ with other anti-neoplastic agents promoted the efficacy of existing cancer treatments. Further research is needed to acquire a more comprehensive understanding of its exact molecular targets and pathways and maximize its clinical usefulness. These investigations may potentially aid in the development of novel techniques to combat drug resistance and surmount the obstacles presented by chemotherapy and radiotherapy.
Graphical Abstract
... TQ has a relatively low molecular weight, making it easily soluble in organic solvents such as ethanol, methanol, and dimethyl sulfoxide (DMSO). This solubility profile has facilitated its use in various in vitro studies [37].Studies have suggested that TQ's moderate to low bioavailability is due to factors such as poor aqueous solubility, rapid metabolism, and limited gastrointestinal absorption [38]. Strategies to enhance the bioavailability of TQ have been explored, including the development of novel formulations, such as nanostructured lipid carriers or encapsulation in liposomes, to improve its stability and absorption [39]. ...
Colorectal cancer (CRC) remains a significant health concern worldwide. The toxicities associated with the current treatment modalities for CRC and the growing emergence of chemotherapeutic resistance underscores the need for the discovery of novel anti-cancer agents that offer benefits in tackling these issues. Thymoquinone (TQ), a compound derived from Nigella sativa, has shown promising anticancer effects. This study aimed to investigate the anticancer properties of TQ against colorectal cancer (HCT-116) cells in vitro. The anti-cancer potential of TQ was evaluated using immunocytochemistry, cell cycle analysis, and Annexin V/PI apoptotic assay after 48 hours of treatment with TQ, 5-fluorouracil (5-FU) (positive control), and TQ + 5-FU. The results indicated a substantial reduction in (Epidermal growth factor receptor) EGFR expression post-TQ treatment (P ≤ 0.001). Similarly, increased expression of the apoptotic marker Caspase-3 was observed in cells treated with TQ (P ≤ 0.001), 5- FU (P ≤ 0.001), and their combination (P ≤ 0.001). Cell cycle analysis showed increased pre-G1 cell events in 5-FU (7.4%, P ≤ 0.05) and 5-FU + TQ (6.6%, P ≤ 0.05) with a slight elevation seen with TQ (1.7 %, P ≥0.05). Annexin V/PI apoptosis analysis further indicated that TQ-induced early apoptosis (9.15%) and late apoptosis (48.2%) and 5-FU + TQ had 14.5% and 24.8% respectively. In conclusion, Thymoquinone shows anticancer effects against colorectal cancer cells (HCT-116), decreasing EGFR expression and inducing apoptosis as evidenced by pre-G1 cell accumulation and elevated caspase-3 expression. While combined TQ and 5-FU treatment showed certain effects, it did not appear to enhance the anti-cancer activity of TQ or 5-FU, warranting further exploration.
... It exerts various anticancer mechanisms by involving in signaling pathways such as MAPK pathway, PI3K-mTOR pathway, Wnt pathway, and JAK-STAT signaling pathways and also plays a crucial role in the cancer cell cycle (Farooqi, Attar, and Xu 2022). TQ induces apoptosis by downregulating anti-apoptotic proteins like Bcl-2 and Bcl-xL and upregulating pro-apoptotic proteins like Bam and Bax; induces the expression and production of executioner caspases; reduces the production of intracellular ROS levels; and increases the p53 activity in cancer cells (Homayoonfal, Asemi, and Yousef 2022). Several preclinical and clinical trials reported the versatile therapeutic potential of TQ. ...
Nigella sativa L. (black seed or black cumin) belonging to the Ranunculaceae family is an annual flowering plant native to southwest Asia. It has been widely used in traditional medicinal systems and practices such as Siddha, Unani, Ayurveda, and folk medicine for its remarkable medicinal value in treating liver disorders and other illnesses. Especially, the seeds of N. sativa (NS) are rich in essential oils and other phytoconstituents which results in significant pharmacological activities such as antimicrobial, antioxidant, antihypertensive, anti-inflammatory, anticancer, antidiabetic hepatoprotective, immunomodulatory, and neuroprotective properties. Recent pieces of evidence report that the exploration of the phytoconstituents of N. sativa seeds will tremendously improve the significance of herbal and alternative medicine to the existing therapies. In this chapter, we have focused on the compilation of Nigella sativa oil’s (NSO) phytoconstituents, extraction and isolation strategies, various pharmacological activities, and their toxic properties. In addition, thymoquinone was discussed in detail for its significant medicinal properties. Furthermore, we have also discussed the commercially available Nigella sativa L. products and their manufacturers with market value. Exploration of NSO will lead to the identification of valuable pharmaceutically important compounds in near future.
... Because there have been numerous OS therapies over the last four decades, only the five most recent years are considered below. Although many OS therapies have been developed, their individual and combinational mechanisms are dispersed [106]. Therefore, a schematic is drawn to elucidate their recent medicines and therapy mechanisms in OS, as shown in Figure 3. Medicines are used to inhibit and suppress tumorigenesis, metastasis, immune evasion, and chemoresistance via communication mediums [107]. ...
There has been no significant efficacy in treating osteosarcoma (OS) metastasis after nearly four decades of trials. This
motivates us to elucidate OS therapies using their four bidirectional mutation stages. The historical developments and
clinical advancements are briefly described to refresh the OS therapy status quo. However, the main issue of metastasis
remains unresolved, accounting for 90% of pulmonary metastasis deaths. Thus, this metastasis problem is related
to immune evasion and chemoresistance induced after long-term treatment by immunotherapy for tumorigenesis.
Therefore, it is rational to discuss the relationship cycles of mutation stages, including tumorigenesis, metastasis,
immune evasion, and chemoresistance. Even though many combinational and targeted therapies have been developed
to intensify these mutation treatments, successful clinical translations with higher cure rates are still rare. Through
this review, an in-depth understanding of the bidirectional relationship between the four OS mutation stages and their
respective therapies is provided. Herein, we summarise the medicines for treating tumorigenesis, including Collagen
beta (1-O) galactosyl transferase 2 inhibitors, transformer 2β, and ArfGAP with GTPase domain 1, miR-148a and
miR-21-5p extracellular vesicles, and the long non-coding RNA leukemia inhibitory factor receptor antisense RNA1.
Following the medicines for treating metastasis are AXL receptor tyrosine kinase, miR-135a-5p, messenger RNA B-cell
lymphoma-6, transforming growth factor beta 1, T-cell immunoglobulin, and mucin-domain containing protein-3,
suppressor of cytokine signalling-5, cancer susceptibility 15, Krüppel-like factor 3 antisense RNA 1, programmed cell
death 4, autophagy-related gene 5, and Rab22a-NeoF1. Then the medicines for treating immune evasion are N-cadherin,
ubiquitin-specific peptidase 12 inhibitors, latency-associated peptide domain inhibitors, anti-Wnt2 mAb, anti-αvβ8
integrin, hexokinase-2-mediated i-kappa-b-alpha, indoleamine 2,3-dioxygenase inhibitor with NO, and TGF-βRII
with anti-IgG1. Finally, the medicines for treating chemoresistance are Dihydrofolate reductase, folylpoly-γ-glutamate
synthetase, heat shock protein-90AA1, XCT-790, anlotinib tyrosine kinase inhibitor, and insulin-like growth factors 1.
As a result, this contribution is expected to serve as a reference and guide for scientists and clinicians.
... A wide array of distinctive pharmacological as well as medicinal properties have been exerted by it that include but are not limited to antioxidant, anti-inflammatory, analgesic, antihistaminic, anti--Alzheimer's, neuro and hepatoprotective, insecticidal, and so on [18]. Besides exhibiting these significant activities, THY also displays potent antitumor [18] and chemosensitive activity [17] and is further reported to decrease the toxic effects that arise with the use of conventional chemotherapeutic drugs [19]. Mechanistically, the anticancer activity of THY is being exerted by disturbing various cellular processes that include apoptosis, proliferation, angiogenesis, and cell cycle, along with tumorigenic functions such as metastasis, migration of cells, and invasion [20]. ...
... In the case of breast cancer, for example, TQ has been observed to increase the expression of p53, a vital tumor-suppressor gene, in a time-dependent manner. This upregulation of p53 promotes apoptosis and inhibits the proliferation of cancer cells [24]. In acute myeloid leukemia cells, TQ has been shown to re-express tumor-suppressor genes through de-methylation, inhibit the enzymatic activity of JAK/STAT signaling, and induce apoptosis [8]. ...
Leukemia, a condition characterized by the abnormal proliferation of blood cells, poses significant challenges in cancer treatment. Thymoquinone (TQ), a bioactive compound derived from black seed, has demonstrated anticancer properties, including telomerase inhibition and the induction of apoptosis. However, TQ’s poor solubility and limited bioavailability hinder its clinical application. This study explored the use of Sulfobutylether-β-cyclodextrin (SBE-β-CD), a cyclodextrin derivative, to enhance the solubility and stability of TQ for leukemia treatment. SBE-β-CD offers low hemolytic activity and has been successfully employed in controlled drug release systems. The study investigated the formation of inclusion complexes between TQ and SBE-β-CD and evaluated their effects on leukemia cell growth and telomerase activity. The results indicated that the TQ/SBE-β-CD complex exhibited improved solubility and enhanced cytotoxic effects against K-562 leukemia cells compared to TQ alone, suggesting the potential of SBE-β-CD as a drug delivery system for TQ. The annexin V-FITC assay demonstrated increased apoptosis, while the qPCR quantification assay revealed reduced telomerase activity in leukemia cells treated with TQ/SBE-β-CD, supporting its anti-leukemic potential. The molecular docking analysis indicated a strong binding affinity between TQ and telomerase. However, further research is needed to optimize the apoptotic effects and minimize necrosis induction. In conclusion, TQ/SBE-β-CD shows promise as a novel strategy for leukemia treatment by inhibiting telomerase and enhancing the cytotoxic effects of TQ, offering a potential solution to overcome the limitations of TQ’s poor solubility and bioavailability.
