Colon cancer and Seed nutrition

Dr. Weeks’ Comment: Whole black cumin seeds as we as its extract thymoquinol (TQ) have anti-cancer benefits in general and quite impressively, against colon cancer in particular. Eat the Seeds to obtain optimal nutrition and all the health benefits of the organic and non-GMO seeds.  

 

“…Thymoquinone (TQ) is used to treat different cancers, including colon cancer…”

“…These in vivo results support the notion that TQ may be of value as a chemo-preventive alternative in colorectal cancer patients…”

“…The anti-tumor effects of thymoquinone have also been investigated in tumor xenograft mice models for colon, prostate, pancreatic and lung cancerThe combination of thymoquinone and conventional chemotherapeutic drugs could produce greater therapeutic effect as well as reduce the toxicity of the latter…”

“…Recent studies revealed a protective effect of thymoquinone, a non-toxic constituent of the essential oil of Nigella sativa, against doxorubicin-induced cardiotoxicity…”

 

J Agric Food Chem. 2015 Feb 11;63(5):1540-6. doi: 10.1021/jf5054063. Epub 2015 Feb 3.

Thymoquinone Induces Caspase-Independent, Autophagic Cell Death in CPT-11-Resistant LoVo Colon Cancer via Mitochondrial Dysfunction and Activation of JNK and p38.

Chemotherapy causes unwanted side effects and chemoresistance, limiting its effectiveness. Therefore, phytochemicals are now used as alternative treatments. Thymoquinone (TQ) is used to treat different cancers, including colon cancer. The irinotecan-resistant (CPT-11-R) LoVo colon cancer cell line was previously constructed by stepwise CPT-11 challenges to untreated parental LoVo cells. TQ dose-dependently increased the total cell death index and activated apoptosis at 2 μM, which then diminished at increasing doses. The possibility of autophagic cell death was then investigated. TQ caused mitochondrial outer membrane permeability (MOMP) and activated autophagic cell death. JNK and p38 inhibitors (SP600125 and SB203580, respectively) reversed TQ autophagic cell death. TQ was also found to activate apoptosis before autophagy, and the direction of cell death was switched toward autophagic cell death at initiation of autophagosome formation. Therefore, TQ resulted in caspase-independent, autophagic cell death via MOMP and activation of JNK and p38 in CPT-11-R LoVo colon cancer cells.

 

 

2.
Oncol Rep. 2014 Aug;32(2):821-8. doi: 10.3892/or.2014.3223. Epub 2014 May 29.

Thymoquinone induces apoptosis in human colon cancer HCT116 cells through inactivation of STAT3 by blocking JAK2- and Src”‘mediated phosphorylation of EGF receptor tyrosine kinase.

Thymoquinone (TQ), a compound isolated from black seed oil (Nigella sativa), has been reported to possess anti-inflammatory and anticancer activities. However, the molecular mechanisms underlying the anticancer effects of TQ remain poorly understood. In the present study, we found that TQ significantly reduced the viability of human colon cancer HCT116 cells in a concentration- and time-dependent manner. Treatment of cells with TQ induced apoptosis, which was associated with the upregulation of Bax and inhibition of Bcl-2 and Bcl-xl expression. TQ also activated caspase-9,-7, and -3, and induced the cleavage of poly-(ADP-ribose) polymerase (PARP). Pretreatment with a pan-caspase inhibitor, z-VAD-fmk, abrogated TQ-induced apoptosis by blocking the cleavage of caspase-3 and PARP. Treatment of cells with TQ also diminished the constitutive phosphorylation, nuclear localization and the reporter gene activity of signal transducer and activator of transcription-3 (STAT3). TQ attenuated the expression of STAT3 target gene products, such as survivin, c-Myc, and cyclin-D1, -D2, and enhanced the expression of cell cycle inhibitory proteins p27 and p21. Treatment with TQ attenuated the phosphorylation of upstream kinases, such as Janus-activated kinase-2 (JAK2), Src kinase and epidermal growth factor receptor (EGFR) tyrosine kinase. Pharmacological inhibition of JAK2 and Src blunted tyrosine phosphorylation of EGFR and STAT3, while treatment with an EGFR tyrosine kinase inhibitor gefitinib inhibited phosphorylation of STAT3 without affecting that of JAK2 and Src in HCT116 cells. Collectively, our study revealed that TQ induced apoptosis in HCT116 cells by blocking STAT3 signaling via inhibition of JAK2- and Src-mediated phosphorylation of EGFR tyrosine kinase.

 

 

3.

Eur J Cancer. 2013 Mar;49(5):1127-35. doi: 10.1016/j.ejca.2012.10.007. Epub 2012 Nov 3.

Effect of thymoquinone on 1,2-dimethyl-hydrazine-induced oxidative stress during initiation and promotion of colon carcinogenesis.

We evaluated pre- and post-thymoquinone (TQ) treatment on 1,2-dimethyl-hydrazine (DMH)-induced oxidative stress during initiation and promotion of colon carcinogenesis. Wistar rats were induced with DMH (20mg/kg) for 10 or 20 weeks, and treated with TQ (5mg/kg). Following sacrifice, the colons were analysed for tumour development, reactive oxygen species (ROS) generation, lipid peroxidation [conjugated diene (CD) and malondialdehyde (MDA)], antioxidants [glutathione peroxidase (GPx), catalase (CAT), superoxide dismutase (SOD) and reduced glutathione (GSH)], and histological changes. Increased ROS levels and lipid peroxidation were seen during tumour initiation and promotion. All ROS-scavenging enzyme activities were increased upon shorter DMH treatment but not following longer treatment, while GSH amount was increased upon both treatments. Oxidative state perturbations were associated with moderate colon dysplasia and 30% tumour incidence at initiation and marked dysplasia and 100% tumour incidence at promotion. TQ pre-treatment restored completely DMH-induced oxidative stress at initiation and established histological changes and tumour development. It also abrogated oxidative status aggravation at promotion, and significantly reduced tumour incidence (67%). By comparison, TQ post-treatment corrected oxidative status and attenuated tumour development at initiation. It slightly reduced MDA and antioxidant level at promotion, with a slight reduction in tumour state and dysplasia degree. TQ is efficacious in protecting and curing DMH-induced initiation phase ofcolon cancer, while exerting a protective role at promotion. TQ effect seems to be related to its capacity in preventing DMH-induced oxidative stress. These in vivo results support the notion that TQ may be of value as a chemo-preventive alternative in colorectal cancer patients.

 

4.

Fundam Clin Pharmacol. 2013 Oct;27(5):557-69. doi: 10.1111/j.1472-8206.2012.01056.x. Epub 2012 Jul 13.

Thymoquinone as an anticancer agent: evidence from inhibition of cancer cells viability and invasion in vitro and tumor growth in vivo.

Phytochemical compounds are emerging as a new generation of anticancer agents with limited toxicity in cancer patients. The purpose of this study was to investigate the potential impact of thymoquinone (TQ), the major constituent of black seed, on survival, invasion of cancer cells in vitro, and tumor growth in vivo. Exposure of cells derived from lung (LNM35), liver (HepG2), colon (HT29), melanoma (MDA-MB-435), and breast (MDA-MB-231 and MCF-7) tumors to increasing TQ concentrations resulted in a significant inhibition of viability through the inhibition of Akt phosphorylation leading to DNA damage and activation of the mitochondrial-signaling proapoptotic pathway. We provide evidence that TQ at non-toxic concentrations inhibited the invasive potential of LNM35, MDA-MB-231, and MDA-MB231-1833 cancer cells. Moreover, we demonstrate that TQ synergizes with DNA-damaging agent cisplatin to inhibit cellular viability. The anticancer activity of thymoquinone was also investigated in athymic mice inoculated with the LNM35 lung cells. Administration of TQ (10 mg/kg/i.p.) for 18 days inhibited the LNM35 tumor growth by 39% (P < 0.05). Tumor growth inhibition was associated with significant increase in the activated caspase-3. The in silico target identification suggests several potential targets of TQ mainly HDAC2 proteins and the 15-hydroxyprostaglandin dehydrogenase. In this context, we demonstrated that TQ treatment resulted in a significant inhibition of HDAC2 proteins. In view of the available experimental findings, we contend thatthymoquinone and/or its analogues may have clinical potential as an anticancer agent alone or in combination with chemotherapeutic drugs such as cisplatin.

 

5.
Biochem Pharmacol. 2012 Feb 15;83(4):443-51. doi: 10.1016/j.bcp.2011.09.029. Epub 2011 Oct 10.

Thymoquinone: potential cure for inflammatory disorders and cancer.

Thymoquinone is an active ingredient isolated from Nigella sativa and has been investigated for its anti-oxidant, anti-inflammatory and anticancer activities in both in vitro and in vivo models since its first extraction in 1960s. Its anti-oxidant/anti-inflammatory effect has been reported in various disease models, including encephalomyelitis, diabetes, asthma and carcinogenesis. Moreover, thymoquinone could act as a free radical and superoxide radical scavenger, as well as preserving the activity of various anti-oxidant enzymes such as catalase, glutathione peroxidase and glutathione-S-transferase. The anticancer effect(s) of thymoquinone are mediated through different modes of action, including anti-proliferation, apoptosis induction, cell cycle arrest, ROS generation and anti-metastasis/anti-angiogenesis. In addition, this quinone was found to exhibit anticancer activity through the modulation of multiple molecular targets, including p53, p73, PTEN, STAT3, PPAR-γ, activation of caspases and generation of ROS. The anti-tumor effects of thymoquinone have also been investigated in tumor xenograft mice models for colon, prostate, pancreatic and lung cancer. The combination of thymoquinone and conventional chemotherapeutic drugs could produce greater therapeutic effect as well as reduce the toxicity of the latter. In this review, we summarize the anti-oxidant/anti-inflammatory and anticancer effects of thymoquinone with a focus on its molecular targets, and its possible role in the treatment of inflammatory diseases and cancer.

 

 

6.
Cancer Chemother Pharmacol. 2011 Apr;67(4):867-74. doi: 10.1007/s00280-010-1386-x. Epub 2010 Jun 26.

Combinatorial effects of thymoquinone on the anti-cancer activity of doxorubicin.

PURPOSE:

Doxorubicin is a mainstay of cancer chemotherapy despite its clinical limitations that arise from its cardiotoxicity and the high incidence of multi-drug resistance. Recent studies revealed a protective effect of thymoquinone, a non-toxic constituent of the essential oil of Nigella sativa, against doxorubicin-induced cardiotoxicity. We now investigated the influence of thymoquinone on various other effects exerted by doxorubicin in human cancer cells.

METHODS:

Doxorubicin, thymoquinone and equimolar mixtures of both were tested for cytotoxicity on human cells of HL-60 leukaemia, 518A2 melanoma, HT-29 colon, KB-V1 cervix, and MCF-7 breast carcinomas as well as multi-drug-resistant variants thereof and on non-malignant human fibroblasts (HF). Apoptosis induction was analysed via DNA fragmentation, activity studies of the caspases-3, -8 and -9, determination of changes in the mitochondrial membrane potential and in the ratio of the mRNA expressions of pro- and anti-apoptotic proteins bax and bcl-2. The generation of reactive oxygen species (ROS) was assessed by the NBT assay.

RESULTS:

Thymoquinone improved the anti-cancer properties of doxorubicin in a cell line-specific manner. We found a significant rise of the growth inhibition by doxorubicin in HL-60 and multi-drug-resistant MCF-7/TOPO cells when thymoquinone had been added. The mode of action of both drugs and of their mixture was mainly apoptotic. In HL-60 cells, the drug mixture caused an additional concentration maximum of effector caspase-3 not observed for either of the pure drugs. The impact of the drug mixture on the mitochondria of HL-60 cells was also greater than those of the individual quinones alone. In addition, the drug mixture led to a higher concentration of reactive oxygen species in HL-60 cells.

CONCLUSIONS:

In summary, thymoquinone is a booster for the anti-cancer effect of doxorubicin in certaincancer cell lines. Distinct improvements on efficacy, selectivity, and even breaches of multi-drug resistance were observed for equimolar mixtures of doxorubicin and thymoquinone.

 

7.
Exp Ther Med. 2010 Mar;1(2):369-375. Epub 2010 Mar 1.

Thymoquinone hydrazone derivatives cause cell cycle arrest in p53-competent colorectal cancer cells.

Thymoquinone (TQ), the major compound of black seed oil, has been shown to induce pro-apoptotic signaling pathways in various human cancer models. Although TQ is commonly used in traditional medicine, its use in humans is limited due to its chemical properties and poor membrane penetration capacity. We therefore attached saturated and unsaturated fatty acid residues to TQ and evaluated the effect on cell proliferation, apoptosis and underlying signaling pathways in HCT116 and HCT116(p53-/-) colon cancer and HepG2 hepatoma cells in vitro. Treatment with thymoquinone-4-α-linolenoylhydrazone (TQ-H-10) or thymoquinone-4-palmitoylhydrazone (TQ-H-11) induced a cytostatic effect, particularly in p53-competent HCT116 cells, mediated by an up-regulation of p21(cip1/waf1) and a down-regulation of cyclin E, and associated with an S/G(2) arrest of the cell cycle. Cells lacking p53 (HCT116(p53-/-)) or HepG2 liver cancer cells showed only a minor response to TQ-H-10. These findings demonstrate that derivatives of TQ inhibit cell proliferation dependent on p53 status by activating the cell cycle inhibitor p21(cip1/waf1) at lower concentrations than unmodified TQ. Structural modifications can therefore contribute to the further clinical development of TQ.

 

 

8.
Cancer Res. 2008 Jul 15;68(14):5609-18. doi: 10.1158/0008-5472.CAN-08-0884.

Thymoquinone triggers inactivation of the stress response pathway sensor CHEK1 and contributes to apoptosis in colorectal cancer cells.

There are few reports describing the role of p53-dependent gene repression in apoptotic cell death. To identify such apoptosis-associated p53 target genes, we used the pro-oxidant plant-derived drug thymoquinone and compared p53+/+ and p53-/- colon cancer cells HCT116. The p53 wild-type (wt) status correlated with more pronounced DNA damage and higher apoptosis after thymoquinone treatment. A significant up-regulation of the survival gene CHEK1 was observed in p53-/- cells in response to thymoquinone due to the lack of transcriptional repression of p53. In p53-/- cells, transfection with p53-wt vector and CHEK1 small interfering RNA treatment decreased CHEK1 mRNA and protein levels and restored apoptosis to the levels of the p53+/+ cells. p53-/- cells transplanted to nude mice treated with thymoquinone up-regulated CHEK1 expression and did not undergo apoptosis unlike p53+/+ cells. Immunofluorescence analysis revealed that the apoptosis resistance in p53-/- cells after thymoquinone treatment might be conveyed by shuttling of CHEK1 into the nucleus. We confirmed the in vivo existence of this CHEK1/p53 link in human colorectal cancer, showing that tumors lacking p53 had higher levels of CHEK1, which was accompanied by poorer apoptosis. CHEK1 overexpression was correlated with advanced tumor stages (P = 0.03), proximal tumor localization (P = 0.02), and worse prognosis (1.9-fold risk, univariate Cox regression; Kaplan-Meier, P = 0.04). We suggest that the inhibition of the stress response sensor CHEK1 might contribute to the antineoplastic activity of specific DNA-damaging drugs.

 

 

9.
Phytother Res. 2008 Oct;22(10):1311-23. doi: 10.1002/ptr.2487.

Role of Nigella sativa and a number of its antioxidant constituents towards azoxymethane-induced genotoxic effects and colon cancer in rats.

This study examined the chemopreventive effect of Nigella sativa and some of its antioxidant constituents on a number of colon cancer biomarkers in rats induced with azoxymethane (AOM). Sixty male Sprague-Dawley rats were randomly assigned into ten subgroups: vehicle (1-5) and experimental (6-10). The rats in each group were fed one of the following diets: basal diet, (200 mg/kg) Nigella sativa, (0.2 mg/kg) selenium, (1.2 mg/kg) all-trans-retinol plus (100 mg/kg) DL-alpha-tocopherol and (10 mg/kg) thymoquinone, respectively. Only rats in subgroups 6-10 were injected with AOM (15 mg/kg) once per week for 2 weeks. Both groups were fed their respective diets for 5 weeks. Then they were killed and examined for colonic aberrant crypt foci (ACF). Our result showed that only vitamin supplementation was effective on ACF. Nigella sativa revealed inhibitory effects only on DNA damage (day 34) in the AOM-treated rat group. Alternatively, selenium, thymoquinone and vitamins inhibited the MDA content in the liver. Although the exact mechanisms involved in the protective role of Nigella sativa against the initiation of colon carcinogenesis are not clearly understood, the results suggest that its inhibitory effects might depend on the combined competitive inhibition of various antioxidant constituents of this plant.

 

 

10.
J Cell Mol Med. 2008 Jan-Feb;12(1):330-42. doi: 10.1111/j.1582-4934.2007.00095.x.

Thymoquinone reduces mouse colon tumor cell invasion and inhibits tumor growth in murine colon cancer models.

We have shown that thymoquinone (TQ) is a potent antitumor agent in human colorectal cancer cells. In this study, we evaluated TQ’s therapeutic potential in two different mice colon cancer models [1,2-dimethyl hydrazine (DMH) and xenografts]. We also examined TQ effects on the growth of C26 mouse colorectal carcinoma spheroids and assessed tumor invasion in vitro. Mice were treated with saline, TQ, DMH, or combinations once per week for 30 weeks and the multiplicity, size and distribution of aberrant crypt foci (ACF) and tumors were determined at weeks 10, 20 and 30. TQ injected intraperitoneally (i.p.) significantly reduced the numbers and sizes of ACF at week 10; ACF numbers were reduced by 86%. Tumor multiplicity was reduced at week 20 from 17.8 in the DMH group to 4.2 in mice injected with TQ. This suppression was observed at week 30 and was long-term; tumors did not re-grow even when TQ injection was discontinued for 10 weeks. In a xenograft model of HCT116 colon cancer cells, TQ significantly (P < 0.05) delayed the growth of the tumor cells. Using a matrigel artificial basement membrane invasion assay, we demonstrated that sub-cyto-toxic doses of TQ (40 microM) decreased C26 cell invasion by 50% and suppressed growth in three-dimensional spheroids. Apoptotic signs seen morphologically were increased significantly in TQ-treated spheroids. TUNEL staining of xenografts and immunostaining for caspase 3 cleavage in DMH tumors confirmed increased apoptosis in mouse tumors in response to TQ. These data should encourage further in vivo testing and support the potential use of TQ as a therapeutic agent in human colorectal cancer.

 

 

11.
Biomed Sci Instrum. 2007;43:272-7.

A comparison of 5-fluorouracil and natural chemotherapeutic agents, EGCG andthymoquinone, delivered by sustained drug delivery on colon cancer cells.

While 5-fluorouracil continues to be the chemotherapeutic gold-standard for the treatment of colon cancer, the side effects of 5-FU are numerous due to its ability to attack both healthy and cancerous cells. However, research continues to provide positive findings in regards to antioxidants and their success in deterring certain disease processes, especially cancer. Epigallocatechin-3-gallate (EGCG), the most abundant catechin found in green tea, is a valuable scavenger of reactive oxygen species in vitro as well as in vivo. Thymoquinone(TQ), the major active component of Nigella sativa (black seed), is also known for its powerful scavenger abilities as an inhibitor of oxidative stress and has been utilized in the Middle East for centuries because of its capability to heal many different diseases. Therefore, the objective of this study was to investigate the role of sustained drug delivery of TQ, EGCG, and 5-FU on the metabolic activity as well as structural changes in the SW-626 human colon cancer cell line in culture. Results of this study indicate a sustained drug delivery of EGCG and TQ demonstrated significant (p < 0 .01) cellular destruction and interference of cellular metabolic functions of SW-626 human colon cancer cells, which was comparable to SW-626 cells exposed to sustained drug delivery of 5-FU. Furthermore, MDA, glutathione, and nitric oxide all revealed significant alterations (p<0.05) as early as 24 hours. Morphologically, cellular changes occurred after exposure to TQ and EGCG at 24 hours which were also comparable to cells exposed to 5-FU. The delivery of the natural agents may offer a safe alternative treatment in for colon cancer.
NOTE:   the ground up whole seed is much more beneficial than the extracted seed oils which become rancid.  The whole seed, when ground up, has ligands and bioflavanoids from the seed husks which protect the oils from oxidizing.  

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Dr. Weeks’ Comment: Whole black cumin seeds as we as its extract thymoquinol (TQ) have anti-cancer benefits in general and quite impressively, against colon cancer in particular. Eat the Seeds to obtain optimal nutrition and all the health benefits of the organic and non-GMO seeds.     “…Thymoquinone (TQ) is used to treat different cancers, including colon cancer…”…
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