•This year marks 50 years since thymoquinone was isolated from black seed.•Thymoquinone has had a long history of battling cancer in vitro and in vivo.•Thymoquinone modulates nine of the ten ...hallmarks of cancer.•There are no controlled Phase I clinical studies on thymoquinone in human tumors.
Thymoquinone (TQ), the main active constituent of black seed essential oil, exhibits promising effects against inflammatory diseases and cancer. TQ, modulates signaling pathways that are key to cancer progression, and enhances the anticancer potential of clinical drugs while reducing their toxic side effects. Considering that TQ was isolated 50 years ago, this review focuses on TQ's chemical and pharmacological properties and the latest advances in TQ analog design and nanoformulation. We discuss our current state of knowledge of TQ's adjuvant potential and in vivo antitumor activity and highlight its ability to modulate the hallmarks of cancer.
Reviewing the anticancer effects and underlying molecular targets of thymoquinone, a molecule with promising biological activities that was isolated 50 years ago, is of crucial importance for its clinical translation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Colorectal cancer causes 0.5 million deaths each year. To combat this type of cancer the development of new specific drug candidates is urgently needed. In the present work seven novel ...thymoquinone–artemisinin hybrids with different linkers were synthesized and tested for their in vitro anticancer activity against a panel of various tumor cell lines. The thymoquinone–artesunic acid hybrid 7 a, in which both subunits are connected via an ester bond, was found to be the most active compound and selectively decreased the viability of colorectal cancer cells with an IC50 value of 2.4 μm (HCT116) and 2.8 μm (HT29). Remarkably, hybrid 7 a was up to 20‐fold more active than its parent compounds (thymoquinone and artesunic acid), while not affecting nonmalignant colon epithelial HCEC cells (IC50>100 μm). Moreover, the activity of hybrid 7 a was superior to that of various 1:1 mixtures of thymoquinone and artesunic acid. Furthermore, hybrid 7 a was even more potent against both colon cancer cell lines than the clinically used drug 5‐fluorouracil. These results are another excellent proof of the hybridization concept and confirm that the type and length of the linker play a crucial role for the biological activity of a hybrid drug. Besides an increase in reactive oxygen species (ROS), elevated levels of the DNA‐damage marker γ‐H2AX were observed. Both effects seem to be involved in the molecular mechanism of action for hybrid 7 a in colorectal cancer cells.
Half a million deaths are caused annually by colorectal cancer. Therefore, the development of new drug candidates is urgently needed. In this study, seven novel thymoquinone–artemisinin hybrids with different linkers were synthesized and tested for their activity against various tumor cell lines. One hybrid emerged as being particularly potent (outperforming the clinical reference drug 5‐fluorouracil) and specific for colon tumor cells, confirming that the nature and length of the linker play crucial roles for the biological activity of a hybrid drug.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
The main objective of this study was to identify predictors of Complementary and Alternative Medicine (CAM) use in Lebanon. Data for this study were drawn from a national survey conducted among ...Lebanese adults (n=1500). A modified version of the Social Behavioral Model (SBM) was used to understand CAM use in the study population. In this version, predisposing factors included sociodemographic characteristics (age, gender, education, and employment) and Push and Pull factors. Additionally, enabling resources included income, and medical need encompassed presence of chronic disease and perceived health status. Simple and multiple logistic regressions were used to examine the predictors of CAM use in the study population. Results of the multiple logistic regression showed that younger and older adults were less likely to use CAM as compared to middle-aged respondents. The Push factor “dissatisfaction with conventional medicine” was associated with higher odds of CAM use. For three of the six Pull factors, compared to participants who strongly disagreed, those who had a tendency of taking care of one’s health were more likely to use CAM. Income and presence of chronic disease were also associated with higher odds of CAM use. The findings of this study affirmed the utility of the SBM in explaining the use of CAM and proposed a new version of this model, whereby the Push and Pull factors are integrated within the predisposing factors of this model.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK, VSZLJ
Glioblastoma Multiforme (GBM) is the most aggressive form of malignant brain tumor. The median survival rate does not exceed two years, indicating an imminent need to develop novel therapies. The ...atypical adamantyl retinoid ST1926 induces apoptosis and growth inhibition in different cancer types. We have shown that ST1926 is an inhibitor of the catalytic subunit of DNA polymerase alpha (POLA1), which is involved in initiating DNA synthesis in eukaryotic cells. POLA1 levels are elevated in GBM versus normal brain tissues. Therefore, we studied the antitumor effects of ST1926 in several human GBM cell lines. We further explored the global protein expression profiles in GBM cell lines using liquid chromatography coupled with tandem mass spectrometry to identify new targets of ST1926. Low sub-micromolar concentrations of ST1926 potently decreased cell viability, induced cell damage and apoptosis, and reduced POLA1 protein levels in GBM cells. The proteomics profiles revealed 197 proteins significantly differentially altered upon ST1926 treatment of GBM cells involved in various cellular processes. We explored the differential gene and protein expression of significantly altered proteins in GBM compared to normal brain tissues.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Colorectal cancer (CRC) is one of the leading cancers and causes of death in patients. 5-fluorouracil (5-FU) is the therapy of choice for CRC, but it exhibits high toxicity and drug resistance. ...Tumorigenesis is characterized by a deregulated metabolism, which promotes cancer cell growth and survival. The pentose phosphate pathway (PPP) is required for the synthesis of ribonucleotides and the regulation of reactive oxygen species and is upregulated in CRC. Mannose was recently reported to halt tumor growth and impair the PPP. Mannose inhibitory effects on tumor growth are inversely related to the levels of phosphomannose isomerase (PMI). An in silico analysis showed low PMI levels in human CRC tissues. We, therefore, investigated the effect of mannose alone or in combination with 5-FU in human CRC cell lines with different p53 and 5-FU resistance statuses. Mannose resulted in a dose-dependent inhibition of cell growth and synergized with 5-FU treatment in all tested cancer cell lines. Mannose alone or in combination with 5-FU reduced the total dehydrogenase activity of key PPP enzymes, enhanced oxidative stress, and induced DNA damage in CRC cells. Importantly, single mannose or combination treatments with 5-FU were well tolerated and reduced tumor volumes in a mouse xenograft model. In summary, mannose alone or in combination with 5-FU may represent a novel therapeutic strategy in CRC.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Terpenoids are the largest class of natural products, most of which are derived from plants. Amongst their numerous biological properties, their anti-tumor effects are of interest for they are ...extremely diverse which include anti-proliferative, apoptotic, anti-angiogenic, and anti-metastatic activities. Recently, several in vitro and in vivo studies have been dedicated to understanding the ‘terpenoid induced autophagy’ phenomenon in cancer cells. Light has already been shed on the intricacy of apoptosis and autophagy relationship. This latter crosstalk is driven by the delicate balance between activating or silencing of certain proteins whereby the outcome is expressed via interrelated signaling pathways. In this review, we focus on nine of the most studied terpenoids and on their cell death and autophagic activity. These terpenoids are grouped in three classes: sesquiterpenoid (artemisinin, parthenolide), diterpenoids (oridonin, triptolide), and triterpenoids (alisol, betulinic acid, oleanolic acid, platycodin D, and ursolic acid). We have selected these nine terpenoids among others as they belong to the different major classes of terpenoids and our extensive search of the literature indicated that they were the most studied in terms of autophagy in cancer. These terpenoids alone demonstrate the complexity by which these secondary metabolites induce autophagy via complex signaling pathways such as MAPK/ERK/JNK, PI3K/AKT/mTOR, AMPK, NF-kB, and reactive oxygen species. Moreover, induction of autophagy can be either destructive or protective in tumor cells. Nevertheless, should this phenomenon be well understood, we ought to be able to exploit it to create novel therapies and design more effective regimens in the management and treatment of cancer.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
At the dawn of the third millennium, cancer has become the bane of twenty-first century man, and remains a predominant public health burden, affecting welfare and life expectancy globally. Spinal ...osteogenic sarcoma, a primary spinal malignant tumor, is a rare and challenging neoplastic disease to treat. After the conventional therapeutic modalities of chemotherapy, radiation and surgery have been exhausted, there is currently no available alternative therapy in managing cases of spinal osteosarcoma. The defining signatures of tumor survival are characterised by cancer cell ability to stonewall immunogenic attrition and apoptosis by various means. Some of these biomarkers, namely immune-checkpoints, have recently been exploited as druggable targets in osteosarcoma and many other different cancers. These promising strides made by the use of reinvigorated immunotherapeutic approaches may lead to significant reduction in spinal osteosarcoma disease burden and corresponding reciprocity in increase of survival rates. In this review, we provide the background to spinal osteosarcoma, and proceed to elaborate on contribution of the complex ecology within tumor microenvironment giving arise to cancerous immune escape, which is currently receiving considerable attention. We follow this section on the tumor microenvironment by a brief history of cancer immunity. Also, we draw on the current knowledge of treatment gained from incidences of osteosarcoma at other locations of the skeleton (long bones of the extremities in close proximity to the metaphyseal growth plates) to make a case for application of immunity-based tools, such as immune-checkpoint inhibitors and vaccines, and draw attention to adverse upshots of immune-checkpoint blockers as well. Finally, we describe the novel biotechnique of CRISPR/Cas9 that will assist in treatment approaches for personalized medication.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract
Colorectal cancer is the third most common neoplasia and the second cause of cancer-related deaths worldwide. Unlike normal cells, tumor cells reprogram metabolic pathways to meet their ...bioenergetics, redox, biosynthetic demands and rely mostly on aerobic glycolysis (Warburg effect). Colorectal cancer cells upregulate the pentose phosphate pathway (PPP), and p53 is a crucial regulator. The PPP is a significant route for glucose catabolism and is required for DNA synthesis of rapidly-proliferating cells. Its oxidative phase (oxPPP), catalyzed by the rate-limiting enzyme glucose-6-phosphate dehydrogenase (G6PD), provides the cell with nicotinamide adenine dinucleotide phosphate (NADPH) that is needed for biosynthetic and detoxifying processes. For the past six decades, 5-Fluorouracil (5-FU) has been the treatment of choice in colorectal cancer. However, 5-FU exhibits high toxicity and drug resistance in patients. Therefore, we hypothesized that targeting the PPP might offer novel therapeutic opportunities in colorectal cancer and improve the response to 5-FU at lower and safer doses. Accordingly, we aim to investigate and characterize the anti-tumor effect of the G6PD inhibitor, 6-aminonicotinamide (6-AN), alone, or in combination with 5-FU on colorectal cancer cells. We explored the effects of oxPPP inhibition on colorectal cancer cell growth, reactive oxygen species (ROS) production, cell cycle regulation, and senescence. We have shown that 6-AN arrested cell growth in HCT116 and HCT116 p53−/− colorectal cancer cells while spared normal-like colon cells (NCM460D). Moreover, 6-AN induced S-phase arrest and early senescence in HCT116 cells as demonstrated by cell cycle analysis using flow cytometry and senescence-associated beta-galactosidase assay, respectively. We also tested the effects of 6-AN/5-FU combination treatments on cellular viability using MTT assay and validated our results using SRB and trypan blue exclusion assays. Interestingly, combination treatments of 6-AN with 5-FU resulted in synergistic effects as estimated using Compusyn software. We used HCT116 colorectal cancer cells resistant to 5-FU (HCT116 5FU-R) or lacking p53, as models for tumor resistance. Importantly, the combination treatment sensitized both HCT116 p53−/− and HCT116 5FU-R colorectal cancer cells to 5-FU and was accompanied by a reduction in G6PD activity and increased ROS using NBT reduction assay. Our findings indicate that combining 6-AN with 5-FU may decrease resistance and further sensitize colorectal cancer cells to 5-FU treatment independently of p53 and drug resistance status. Exploiting this metabolic vulnerability may offer a novel clinical approach and improve patient's therapy.
Citation Format: Noorhan Ghanem, Chirine El Baba, Lara Al Saleh, Berthe Hayar, Patrick Aouad, Marwa Al Hassan, Riyad El-Khoury, Julnar Usta, Nadine Darwiche. Therapeutic targeting of the pentose phosphate pathway in colorectal cancer abstract. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 236.
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