Black Cumin Seed for Pancreatic Cancer

Dr. Weeks’ Comment: Eating seeds, the most nutrient dense food on earth helps cancer patients be well enough nourished to reclaim their health but certain seeds, like black cumin seed, have powerful anticancer properties. SOUL is a 3 seed drink featuring black cumin seed which many cancer patients are grateful for. Here is the science:


Biomed Pharmacother.
 2018 Oct;106:390-402. doi: 10.1016/j.biopha.2018.06.159. Epub 2018 Jul 11.

Thymoquinone: A novel strategy to combat cancer: A review.

Imran M1Rauf A2Khan IA3Shahbaz M4Qaisrani TB5Fatmawati S6Abu-Izneid T7Imran A8Rahman KU9Gondal TA10.

Abstract

The higher consumption of fruit, herbs, spices, and vegetables is well known and practical strategy to cure human cancers owing to their presence of bioactive compounds. Among these, Nigella sativa is a promising source of bioactive compounds including thymoquinone, monoterpenes, p-cymene and α-piene etc. Thymoquinone has been found effective to inhibit the different cancer stages such as proliferation, migration and invasion. It also acts as anticancer agent against different human cancers such as breast, pancreatic, prostate, blood, oral, bone, head and neck, cervical, liver and lung. It significantly mediated miR-34a up-regulation, enhanced the levels of miR-34a through p53, and down controlled Rac1 expression. Thymoquinone induces apoptosis, regulates the levels of pro- and anti- apoptotic genes. It also has been known to lower the phosphorylation of NF-κB and IKKα/β and reduces the metastasis as well as also lowered the ERK1/2 and PI3K activities. Thymoquinone inhibits the metastasis through activation of JNK and p38. The present review article highlights the anticancer perspectives of thymoquinone in human by various pathways and use of this compound as diet based therapy has proven new pharmacological agent against several types of cancers.

AND THIS STUDY “…Tq as a novel inhibitor of proinflammatory pathways provides a promising strategy that combines anti-inflammatory and proapoptotic modes of action...”

HPB (Oxford). 2009 Aug;11(5):373-81. doi: 10.1111/j.1477-2574.2009.00059.x.

Anti-inflammatory effects of the Nigella sativa seed extract, thymoquinone, in pancreatic cancer cells.

Chehl N1Chipitsyna GGong QYeo CJArafat HA.

Abstract

BACKGROUND:

Both hereditary and sporadic forms of chronic pancreatitis are associated with an increased risk of developing pancreaticductal adenocarcinoma (PDA). Inflammation has been identified as a significant factor in the development of solid tumour malignancies. We have recently shown that thymoquinone (Tq), the major constituent of Nigella sativa oil extract, induced apoptosis and inhibited proliferation in PDA cells. Tq also increased p21 WAF1 expression, inhibited histone deacetylase (HDAC) activity, and induced histone hyperacetylation. HDAC inhibitors have been shown to ameliorate inflammation-associated cancer. In this study, we evaluated the anti-inflammatory potential of Tq in PDA cells in comparison with that of a specific HDAC inhibitor, trichostatin A (TSA).

RESULTS:

Tq dose- and time-dependently significantly reduced PDA cell synthesis of MCP-1, TNF-alpha, interleukin (IL)-1beta and Cox-2. At 24 h, Tq almost completely abolished the expression of these cytokines, whereas TSA had a less dramatic effect. Tq, but not TSA, significantly and dose-dependently reduced the intrinsic activity of the MCP-1 promoter. Tq also inhibited the constitutive and TNF-alpha-mediated activation of NF-kappaB in PDA cells and reduced the transport of NF-kappaB from the cytosol to the nucleus.

CONCLUSIONS:

Our data demonstrate previously undescribed anti-inflammatory activities of Tq in PDA cells, which are paralleled by inhibition of NF-kappaB. Tq as a novel inhibitor of proinflammatory pathways provides a promising strategy that combines anti-inflammatory and proapoptotic modes of action.

Dig Dis Sci. 2015 Apr;60(4):1067-80. doi: 10.1007/s10620-014-3394-x. Epub 2014 Oct 26.

Thymoquinone Pretreatment Overcomes the Insensitivity and Potentiates the Antitumor Effect of Gemcitabine Through Abrogation of Notch1, PI3K/Akt/mTOR Regulated Signaling Pathways in Pancreatic Cancer.

Mu GG1Zhang LLLi HYLiao YYu HG.

Abstract

The gemcitabine-insensitivity remains the main challenge for pancreatic cancer treatment. Thymoquinone, the predominant bioactive ingredient of Nigella sativa, has been shown to possess promising anti-cancer and chemo-sensitizing effects on pancreatic cancer, however, its meticulous mechanism is still indistinct.

RESULTS:

Thymoquinone pretreatment following gemcitabine treatment synergistically caused an increase in pancreatic cancer cells apoptosis and tumor growth inhibition both in vitro and in vivo. The novel combinational regimen also contributes to alterations of multiple molecular signaling targets, such as the suppression of Notch1, NICD accompanying with up-regulation of PTEN, the inactivation of Akt/mTOR/S6 signaling pathways, and the suppression of phosphorylation and nuclear translocation of p65 induced by TNF-α. Thymoquinone pretreatment and gemcitabine also induced down-regulation of anti-apoptotic Bcl-2, Bcl-xL, XIAP and up-regulation and activation of pro-apoptotic molecules including Caspase-3, Caspase-9, Bax and increased release of cytochrome c.

CONCLUSIONS:

This novel modality of thymoquinone pretreatment can enhance the anti-cancer activity of gemcitabine and may be a promising option in the treatment of pancreatic cancer.

BUT THIS was RETRACTED on a technical issue: This article (1) has been retracted at the request of the editors. Following an institutional review by Wayne State University (Detroit, MI), the primary affiliation for several of the authors, it was determined that the Bcl-xL and Mcl-1 bands in Fig. 2A were altered and was unable to verify that the original scanned images represent the experiments described in the article. As a result of these findings, the institution recommended retraction and, upon internal review, the editors agree with this recommendation.

BUT THIS STUDY showing the same effect was NOT retracted

PLoS One. 2014 Sep 8;9(9):e107154. doi: 10.1371/journal.pone.0107154. eCollection 2014.

Synergistic combination of gemcitabine and dietary molecule induces apoptosis in pancreaticcancer cells and down regulates PKM2 expression.

Pandita A1Kumar B2Manvati S1Vaishnavi S1Singh SK3Bamezai RN2.

Gemcitabine, an effective agent in treatment of cancer of pancreas, has undergone failures in many instances after multiple cycles of therapy due to emergence of drug resistance. Combination of dietary compounds with clinically validated drugs has emerged as an effective therapeutic approach to treat pancreatic tumors, refractory to gemcitabine therapy. In order to optimize a possible synergistic combination of Gemcitabine (GCB) with dietary molecules, Betuilnic acid (BA) and Thymoquinone (TQ), stand-alone IC50 dose of GCB, BA and TQ was calculated for pancreatic cancer cell lines. Fixed IC50 dose ratio of the dietary molecules in combination with reduced IC50 dose of GCB was tested on GCB resistant PANC-1 and sensitive MIA PaCa-2 cells for synergism, additive response and antagonism, using calcusyn. Combination index (CI) revealed that pre-treatment of BA and TQ along with GCB synergistically inhibited the cancer cell proliferation in in-vitro experiments. Pyruvate kinase (PK) M2 isoform, a promising target involved in cancer cell metabolism, showed down-regulation in presence of TQ or BA in combination with GCB. GCB with BA acted preferentially on tumor mitochondria and triggered mitochondrial permeability transition. Pre-exposure of the cell lines, MIA PaCa-2 and PANC-1, to TQ in combination with GCB induced apoptosis. Thus, the effectiveness of BA or TQ in combination with GCB to inhibit cell proliferation, induce apoptosis and down-regulate the expression of PKM2, reflects promise in pancreatic cancer treatment.

AND THIS STUDY BELOW:

“…thymoquinone killed approximately 80 percent of the (pancreatic) cancer cells...”

Traditional Herbal Medicine Kills Pancreatic Cancer Cells, 

An herb used in traditional medicine by many Middle Eastern countries may help in the fight against pancreatic cancer, one of the most difficult cancers to treat. Researchers at the Kimmel Cancer at Jefferson in Philadelphia have found that thymoquinone, an extract of Nigella sativa seed oil, blocked pancreatic cancer cell growth and killed the cells by enhancing the process of programmed cell death.

While the studies are in the early stages, the findings suggest that thymoquinone could eventually have some use as a preventative strategy in patients who have gone through surgery and chemotherapy or in individuals who are at a high risk of developing cancer.

According to Hwyda Arafat, M.D., Ph.D., associate professor of Surgery at Jefferson Medical College of Thomas Jefferson University, Nigella sativa helps treat a broad array of diseases, including some immune and inflammatory disorders. Previous studies also have shown anticancer activity in prostate and colon cancers, as well as antioxidant and anti-inflammatory effects.

Using a human pancreatic cancer cell line, she and her team found that adding thymoquinone killed approximately 80 percent of the cancer cells. They demonstrated that thymoquinone triggered programmed cell death in the cells, and that a number of important genes, including p53, Bax, bcl-2 and p21, were affected. The researchers found that expression of p53, a tumor suppressor gene, and Bax, a gene that promotes programmed cell death, was increased, while bcl-2, which blocks such cell death, was decreased. The p21 gene, which is involved in the regulation of different phases of the cell cycle, was substantially increased. She presents her findings May 18 at the Digestive Disease Week in San Diego.

Dr. Arafat and her co-workers also found that thymoquinone caused “epigenetic” changes in pancreatic cancer cells, modifying the cells’ DNA. She explains that these changes involve adding acetyl groups to the DNA structure, specifically to blocks of proteins called histones. This “acetylation” process can be important for genes to be read and translated into proteins. In this case, it could involve the genes that are key to initiating programmed cell death. “We looked at the status of the histones and found surprisingly that thymoquinone increased the acetylation process,” Dr. Arafat says. “We never anticipated that.”

At the same time, adding thymoquinone to pancreatic cancer cells reduced the production and activity of enzymes called histone deacetylases (HDACs), which remove the acetyl groups from the histone proteins, halting the gene transcription process. Dr. Arafat notes that HDAC inhibitors are a “hot” new class of drugs that interfere with the function of histone deacetylases, and is being studied as a treatment for cancer and neurodegenerative diseases. Finding that thymoquinone functions as an HDAC inhibitor, she says, “was very remarkable and really exciting.”

Pancreatic cancer, the fourth-leading cause of cancer death in this country, takes some 34,000 lives a year. The disease frequently is detected after it has spread and only 4 percent of individuals with pancreatic cancer live for five years after diagnosis.

AND THIS STUDY

Adv Prev Med. 2016;2016:1407840. doi: 10.1155/2016/1407840. Epub 2016 Dec 26.

Thymoquinone Promotes Pancreatic Cancer Cell Death and Reduction of Tumor Size through Combined Inhibition of Histone Deacetylation and Induction of Histone Acetylation.

Relles D1Chipitsyna GI2Gong Q1Yeo CJ1Arafat HA2.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is virtually therapy-resistant. As noninvasive lesions progress to malignancy, the precursor period provides a window for cancer therapies that can interfere with neoplastic progression. Thymoquinone (Tq), a major bioactive component of essential oil from Nigella sativa‘s seeds, has demonstrated antineoplastic activities in multiple cancers. In this study, we investigated antineoplastic potential of Tq in human PDAC cell lines, AsPC-1 and MiaPaCa-2. Tq (10-50 μM) inhibited cell viability and proliferation and caused partial G2 cycle arrest in dose-dependent manner in both cell lines. Cells accumulated in subG0/G1 phase, indicating apoptosis. This was associated with upregulation of p53 and downregulation of Bcl-2. Independently of p53, Tq increased p21 mRNA expression 12-fold. Tq also induced H4 acetylation (lysine 12) and downregulated HDACs activity, reducing expression of HDACs 1, 2, and 3 by 40-60%. In vivo, Tq significantly reduced tumor size in 67% of established tumor xenografts (P < 0.05), along with increased H4 acetylation and reduced HDACs expression. Our results showed that Tq mediated posttranslational modification of histone acetylation, inhibited HDACs expression, and induced proapoptotic signaling pathways. These molecular targets demonstrate rationale for using Tq as a promising antineoplastic agent to prevent postoperative cancer recurrence and to prolong survival of PDAC patients after surgical resection.

AND THIS STUDY

Chem Biol Interact. 2015 May 25;233:56-64. doi: 10.1016/j.cbi.2015.03.018. Epub 2015 Apr 1.

Combined effect of microRNA, nutraceuticals and drug on pancreatic cancer cell lines.

Pandita A1Manvati S1Singh SK2Vaishnavi S3Bamezai RN4.

AIM:

We proposed to investigate the combination effect of microRNA, nutraceuticals and drug (MND), in two pancreatic cancer cell lines to assess the therapeutic potential.

MATERIALS AND METHODS:

MIA PaCa-2 and PANC-1 cells transfected with miR-101 or miR-24-2 were treated with Betulinic acid or Thymoquinone and gemcitabine independently and in combination and assessed for the extent of synergism in both experimental and control conditions, considering significance at the p value of <0.05.

RESULTS:

miR-101 or miR-24-2 over-expressing cells when treated with lower than IC50 doses of the dietary compounds and drug showed a reduced (37-50%) viability in two cell lines with differential synergistic effect and the outcome for Pro-caspase3, Poly (ADP-ribose) polymerase (PARP) cleavage and PKM2 expression.

CONCLUSION:

Two independent microRNA backgrounds showed promise in therapeutic intervention of gemcitabine sensitive, MIA PaCa-2 and resistant, PANC-1 pancreatic cancer cells, in combination with dietary agents and drug.

AND THIS STUDY ON MICE with PANCREATIC CANCER CELLS “…Thymoquinone has the anti-neoplastic and anti-metastatic effects on the human pancreatic carcinoma in nude mice. And the above effects may be correlated with the down-regulated expressions of XIAP and MMP-9…”

Zhonghua Yi Xue Za Zhi. 2011 Nov 29;91(44):3111-4.

[Inhibitory effects of thymoquinone on human pancreatic carcinoma orthotopically implanted in nude mice].

[Article in Chinese]Wang YM1.

Abstract

OBJECTIVE:

To explore the anti-neoplastic and anti-metastatic effects of thymoquinone on the model of human pancreatic carcinoma established by surgical orthotopic implantation (SOI) in nude mice.

METHODS:

After a 3-week implantation, 40 mice were randomized into 4 groups: control group, feed with 1% ethanol; low-dose thymoquinone group (L-TQ 5 mg/kg BW daily by i.g.), high-dose thymoquinone group (H-TQ 20 mg/kg BW daily by i.g.) and gemcitabine group (GEM 100 mg/kg BW twice a week by i.p.) (n = 10 each). All treatment sessions lasted for 2 weeks. At Week 8 post-implantation, tumor weight, inhibition rate and the presence of metastasis were evaluated respectively after sacrificing. Immunohistochemistry was used to detect the positive expressions of Ki-67, XIAP (X-linked inhibitor of apoptosis protein) and MMP-9 (matrix metalloproteinase 9) in tumors.

RESULTS:

The tumor growth-inhibiting rates of L-TQ group, H-TQ group and GEM group were 42.57%, 64.11% and 54.77% respectively. The rates of metastasis in L-TQ group and H-TQ group were 60% and 50% versus GEM group (100%). And the differences had statistical significance (P < 0.05). The positive rates of Ki-67 in group L-TQ and group H-TQ were 37% ± 3% and 32% ± 2% versus group GEM (55% ± 4%). And the differences had statistical significance (P < 0.05). The positive rates of XIAP in group L-TQ and group H-TQ were 30% ± 3% and 28% ± 5% versus group GEM (56% ± 4%). And the differences had statistical significance (P < 0.05). The positive rates of MMP-9 in group L-TQ and group H-TQ were 57% ± 7% and 53% ± 2% versus group GEM (73% ± 4%). And the differences had statistical significance (P < 0.05).

CONCLUSION:

Thymoquinone has the anti-neoplastic and anti-metastatic effects on the human pancreatic carcinoma in nude mice. And the above effects may be correlated with the down-regulated expressions of XIAP and MMP-9.

AND THIS STUDY “…TQ has potential for the development of novel therapies against pancreatic cancer...”

Mol Cancer Ther. 2010 May;9(5):1419-31. doi: 10.1158/1535-7163.MCT-10-0075. Epub 2010 Apr 27.

Effects of thymoquinone in the expression of mucin 4 in pancreatic cancer cells: implications for the development of novel cancer therapies.

Torres MP1Ponnusamy MPChakraborty SSmith LMDas SArafat HABatra SK.

Author information

Abstract

Pancreatic cancer is one of the most lethal cancers in the world, as it continues to be resistant to any therapeutic approaches. The high molecular weight glycoprotein mucin 4 (MUC4) is aberrantly expressed in pancreatic cancer and contributes to the regulation of differentiation, proliferation, metastasis, and the chemoresistance of pancreatic cancer cells. The absence of its expression in the normal pancreatic ductal cells makes MUC4 a promising target for novel cancer therapeutics. Natural products have been widely investigated as potential candidates in cancer therapies, and thymoquinone (TQ), extracted from the seeds of Nigella sativa, has shown excellent antineoplastic properties in some systems. In the present study, we evaluated the effect of TQ on pancreatic cancer cells and specifically investigated its effect on MUC4 expression. The MUC4-expressing pancreatic cancer cells FG/COLO357 and CD18/HPAF were incubated with TQ, and in vitro functional assays were done. The results obtained indicate that treatment with TQ downregulated MUC4 expression through the proteasomal pathway and induced apoptosis in pancreatic cancer cells by the activation of c-Jun NH(2)-terminal kinase and p38 mitogen-activated protein kinase pathways. In agreement with previous studies, the decrease in MUC4 expression correlated with an increase in apoptosis, decreased motility, and decreased migration of pancreatic cancer cells. MUC4 transient silencing studies showed that c-Jun NH(2)-terminal kinase and p38 mitogen-activated protein kinase pathways are activated in pancreatic cancer cells, indicating that the activation of these pathways by TQ is directly related to the MUC4 downregulation induced by the drug. Overall, TQ has potential for the development of novel therapies against pancreatic cancer.

AND HERE THEY WANT TO CREATE A DRUG FROM THYMOQUINONE which they will claim is better to be able to shut down use of the natural (cheap and non-patented substance) “…Present TQ analogs exhibit superior anti-proliferative activity, excellent chemo-sensitizing activity against pancreatic cancer in vitro and in combination with Gemcitabine...”

Bioorg Med Chem Lett. 2013 May 15;23(10):3101-4. doi: 10.1016/j.bmcl.2013.03.003. Epub 2013 Mar 14.

Synthesis, characterization and anti-tumor activity of novel thymoquinone analogs against pancreatic cancer.

Yusufi M1Banerjee SMohammad MKhatal SVenkateswara Swamy KKhan EMAboukameel ASarkar FHPadhye S.

Abstract

Thymoquinone (TQ), isolated from the seeds of Nigella sativa, show moderate efficacy against pancreatic cancer. In the present work we report synthesis and characterization of novel TQ analogs appended with gallate and fluorogallate pharmacophores and evaluation of their effects against pancreatic cancer cell lines for cell viability and induction of apoptosis. The efficacy of the analogs alone or in combination with Gemcitabine was assessed in vitro. LC-MS spectra of ATQTHB and ATQTFB showed major peaks corresponding to expected M+1 fragment at 316.34 and 322.34 respectively. Molecular docking studies revealed good fit for these analogs in the COX-2 protein cavity with better binding energies compared to parent TQ compound. Present TQ analogs exhibit superior anti-proliferative activity, excellent chemo-sensitizing activity against pancreatic cancer in vitro and in combination with Gemcitabine.

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Dr. Weeks’ Comment: Eating seeds, the most nutrient dense food on earth helps cancer patients be well enough nourished to reclaim their health but certain seeds, like black cumin seed, have powerful anticancer properties. SOUL is a 3 seed drink featuring black cumin seed which many cancer patients are grateful for. Here is the science:…
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