Understanding Pancreatic Cancer

compiled by John G. Connor, M.Ac., L.Ac., edited by Barbara Connor, M.Ac., L.Ac.

Table of Contents

  • Introduction 
  • Research on Natural Compounds Which May be Suppressive Against Pancreatic Cancer
  • Understanding Biomarkers in Pancreatic Cancer 
  • References
Introduction
Individual studies estimate that as many as 69% of US cancer patients employ some type of complementary and alternative medicine, 76% of patients in a study of Midwestern cancer patients and 95% of radiation oncology patients in another study.  (Wargovich et al 2010)

Pancreatic cancer is the fourth leading cause of cancer mortality among both men and women in the United States with a 5-year survival rate of only 4%. (Johnson & de Mejia 2011)

Pancreatic cancer, although infrequent, has a very poor prognosis, making it one of the 4 or 5 most common causes of cancer mortality in developed countries. Its incidence varies greatly across regions, which suggests that lifestyle factors such as diet, and environmental factors, such as vitamin D exposure, play a role. Because pancreatic cancer is strongly age-dependent, increasing population longevity and ageing will lead to an increase of the global burden of pancreatic cancer in the coming decades. Smoking is the most common known risk factor, causing 20-25% of all pancreatic tumors. Although a common cause of pancreatitis, heavy alcohol intake is associated only with a modest increased risk of pancreatic cancer. A family history of pancreatic cancer is associated with an increased risk of pancreatic cancer and it is estimated that 5-10% of patients with pancreatic cancer have an underlying germline disorder. Having a non-O blood group, another inherited characteristic, has also been steadily associated with an increased risk of pancreatic cancer. While many risk factors for pancreatic cancer are not modifiable, adopting a healthy lifestyle could substantially reduce pancreatic cancer risk. (Maisonneuve and Lowenfels 2010)

Among many solid tumors, pancreatic cancer has the worst prognosis, and inflammation has been identified as a significant factor in the development of pancreatic malignancy. Several cytokines, reactive oxygen species (ROS) and mediators of inflammatory pathway such as activation of nuclear factor-kappaB (NF-kappaB) and COX-2 lead to an increase in cell proliferation, survival, and inhibition of pro-apoptotic pathway, ultimately resulting in tumor angiogenesis, invasion and metastasis. (Sarkar et al 2007)

Over the past two decades, numerous efforts have been made in improving treatment and survival in PC (pancreatic cancer) patients but the outcome has been disappointing. This disappointing outcome is due to many factors among which de novo resistance (intrinsic) and acquired (extrinsic) resistance to conventional therapeutics (chemotherapy and radiation therapy) including gemcitabine alone or in-combination with other cytotoxic or targeted agents. Emerging evidence suggest that the resistance could in fact be due to the enriched existence of tumor initiating cells, also classified as cancer stem-like cells (CSC) in a tumor mass. The CSCs have the capacity of self-renewal and the potential to regenerate into all types of differentiated cells giving rise to heterogeneous tumor cell populations in a tumor mass, which contributes to tumor aggressiveness. Thus, the failure to eliminate these special cells is considered to be one of the underlying causes of poor treatment outcome with conventional therapeutics, suggesting that newer and novel therapeutic strategies must be developed for the targeted killing of drug resistant CSCs in order to eradicate the risk of tumor recurrence for improving the survival of patients diagnosed with PC. (Bao et al 2011)

It is believed that PC (pancreatic cancer) arises from abnormal tissues or lesions in the pancreas known as pancreatic intra-epithelial neoplasias (PanINs); by stalling the growth of PanINs, we hope to slow the development of, or prevent, PC. COX-2 is an enzyme that is up-regulated by growth factor and inflammatory cytokine-mediated activation of NF-κB in PC . Further studies on breast, colon, and PC have also shown that COX-2 plays a key role in aggressive tumor growth and metastases. Furthermore, we have confirmed that down-regulation of the “master transcription factor,” NF-κB, by natural agents such as TQ (thymoquinone derived from black cumin seed – Nigella sativa – oil) could lead to the sensitization of PC cells to cytotoxic conventional therapeutic agents, especially gemcitabine. (Banerjee et al 2010) 

There is an ever growing interest in treatment with natural compounds as an adjuvant cancer therapy along with conventional cancer therapy. (Virk-Baker et al 2010) For example the combination of a natural VEGF inhibitor along with lower doses of a pharmacological agent may prove helpful in reducing the unwanted side effects of chemotherapy. (Wargovich et al 2010)

Recent evidence shows that pharmaconutrients may act against proliferation, angiogenesis and metastasis in different types of human cancer. (Granci et al 2010)

Research on Natural Compounds Which May be Suppressive Against Pancreatic Cancer

Boswellia – Suppression of CXCR4 (chemokine receptor 4) by AKBA (acetyl-11-keto-β-boswellic acid) was accompanied by the inhibition of pancreatic cancer cell invasion, which is induced by CXCL12, the ligand for CXCR4. In addition, abrogation of the expression of chemokine receptor by AKBA was found in human pancreatic tissues from orthotopic animal model. (Park et al 2011)

Curcumin, docosahexaenoic acid (DHA) – Pancreatic cancer BxPC-3 cells were exposed to curcumin, DHA, or combinations of both and analyzed for proliferation and apoptosis.  Expression and activity of iNOS, COX-2, and 5-LOX are downregulated, and p21 is upregulated in tumor xenograft fed curcumin combined with fish oil diet when compared to individual diets. The preceding results evidence for the first time that curcumin combined with omega-3 fatty acids provide synergistic pancreatic tumor inhibitory properties. (Swamy et al 2008) 

Genistein – We found that genistein inhibited cell growth accompanied by induction of apoptosis with concomitant attenuation of FoxM1 and its downstream genes, such as survivin, cdc25a, MMP-9, and VEGF, resulting in the inhibition of pancreatic cancer cell invasion. (Wang et al 2010)  Asians who consume a diet high in soy products have a relatively low incidence of and mortality due to pancreatic cancer, suggesting that a high intake of soy products may protect people against pancreatic cancer. (Sarkar et al 2002)

Melatonin (MEL) has antioxidant activity and prevents experimental genotoxicity. The specific inhibitor of cyclooxygenase-2 (COX-2), celecoxib (CEL), increases the efficacy of chemoradiotherapy in advanced pancreatic cancer. The objective of the study was the comparison and synergic effect of MEL and CEL during either the induction or progression phases of the tumor process, measuring parameters of oxidative stress, number of tumor nodules and survival of animals with pancreatic cancer. Pancreatic cancer was induced by N-nitrosobis (2-oxopropyl)amine) (BOP) in Syrian hamsters. Melatonin and/or CEL were administered during the induction, postinduction as well as during both phases. The presence of tumor nodules were observed macroscopically in pancreatic and splenic areas, and the levels of lipoperoxides (LPO), reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) in pancreatic tissue were measured. The increases in tumor nodules and LPO as well as the reductions in GSH and enzymatic antioxidants in the pancreas induced by BOP were related to a lower survival rate of animals. The administration of MEL exerted a more potent beneficial effect than CEL treatment on the reduction in tumor nodules, oxidative stress and death of experimental BOP-treated animals. The combined treatment only exerted a synergistic beneficial effect when administered during the induction phase. Melatonin by itself had significant beneficial actions in improving the survival of hamsters. (Padillo et al 2010)

Sulforaphane (SFN) – The broccoli isothiocyanate, sulforaphane (SFN), was recently identified as being capable of eliminating highly therapy-resistant pancreatic carcinoma (PC) cells without inducing toxic side effects. Our studies provide a valuable new mechanistic insight into the SFN-induced elimination of PC cells and suggest that an SFN-enriched diet potentially enhances ROS-releasing chemotherapeutic agents. (Naumann et al 2011) 

Thymoquinone (TQ) – Previously, we were the first to show that Thymoquinone (TQ) derived from black cumin seed (Nigella sativaoil has anti-tumor activity against PC (pancreatic cancer). However, the concentration of TQ required was considered to be high to show this efficacy. Therefore, novel analogs of TQ with lower IC50 are highly desirable. We have synthesized a series of 27 new analogs of TQ by modifications at the carbonyl sites or the benzenoid sites using single pot synthesis and tested their biological activity in PC cells. Among these compounds, TQ-2G, TQ-4A1 and TQ-5A1 (patent pending) were found to be more potent than TQ in terms of inhibition of cell growth, induction of apoptosis and modulation of transcription factor-NF-κB. We also found that our novel analogs were able to sensitize gemcitabine and oxaliplatin-induced apoptosis in MiaPaCa-2 (gemcitabine resistant) PC cells, which was associated with down-regulation of Bcl-2, Bcl-xL, survivin, XIAP, COX-2 and the associated Prostaglandin E2. (Banerjee et al 2010)

Understanding Biomarkers in Pancreatic Cancer 

Bcl-2, BAX, survivin, Ki-67, E-cadherin and S100A2 – Promising markers that emerged for the prediction of overall survival in pancreatic ductal adeoncarcinoma included BAX (HR = 0.31, 95% CI: 0.71-0.56), Bcl-2 (HR = 0.41, 95% CI: 0.27-0.63), survivin (HR = 0.46, 95% CI: 0.29-0.73), Ki-67: (HR = 2.42, 95% CI: 1.87-3.14), COX-2 (HR = 1.39, 95% CI: 1.13-1.71), E-cadherin (HR = 1.80, 95% CI: 1.33-2.42), and S100 calcium-binding proteins, in particular S100A2 (HR = 3.23, 95% CI: 1.58-6.62). (Jamieson et al 2011)

BRCA1 and BRCA2 – are inherited breast cancer tumor suppressor genes that can be recognized on the human genome. BRCA1 and BRCA2 are found on chromosomes 17 and 13 respectively. Inherited mutations of these genes have been found to be associated with an increased risk of familial breast and ovarian cancer occurrences. Carriers of BRCA1 mutations have an increased risk of ovarian cancer (epithelial or transitional cell) and microglandular adenosis, and carriers of BRCA2 are at increased risk for Fanconi’s anemia, pancreatic cancer and prostate cancer. Persons with BRCA1 and BRCA2 mutations have an increased risk of breast cancer. Laboratory Tests and Diagnostic Procedures, p. 255 (2008)

CA 125 – is elevated in cirrhosis, endometriosis, luteal phase of menstrual cycle, menses, neoplasms of the breast, cervix, colon, endometrium, fallopian tube, gastrointestinal tract, liver, lung, lymphoma, non-Hodgkin’s lymphoma, ovary and pancreas, pelvic inflammatory disease, Sjogren’s syndrome and systemic lupus erythematosus. Laboratory Tests and Diagnostic Procedures, p. 273 (2008)

CA-19-9 – The most widely used, and best-recognized, carbohydrate marker of pancreatic cancer is CA 19-9 [CA (carbohydrate antigen) 19-9]. However, the relatively non-specific nature of CA 19-9 limits its routine use in the early diagnosis of pancreatic cancer, but it may be useful in monitoring treatment of pancreatic cancer (e.g. the effectiveness of chemotherapy), as a complement to other diagnostic methods. Some other carbohydrate markers of pancreatic cancer may be considered, such as CEA (carcinoembryonic antigen), CA 50 and CA 242, and the mucins MUC1, MUC2 and MUC5AC, but enzymes involved in the processing of glycoconjugates could also be involved. Our preliminary research shows that the activity of lysosomal exoglycosidases, including HEX (N-acetyl-β-D-hexosaminidase), GAL (β-D-galactosidase), FUC (α-L-fucosidase) and MAN (α-D-mannosidase), in serum and urine may be used in the diagnosis of pancreatic cancer. (Szajda et al 2011)

CTCs – The present study demonstrated that the detection of CTCs in peripheral blood may be useful to predict prognosis in patients with pancreatic cancer (PC). (Kurihara et al 2008)

HER-2/neu Oncogene – Is overexpressed in brain cancer, breast cancer (predictive of poor short- term prognosis, but can benefit from Herceptin therapy), colorectal cancer (predicts poor survival), esophageal cancer, malignant mesothelioma, non-small-cell lung cancer, ovarian cancer, pancreatic adenocarcinomas, endometrial carcinoma, synovial sarcomas and uterine serous papillary carcinoma. HER2/neu is a gene that codes for a transmembrane tyrosine kinase. Amplification of the gene product is noted in up to 30% of breast, ovarian and endometrial carcinomas. Laboratory Tests and Diagnostic Procedures, p. 632-633 ( 2008)

Il-6 (serum) – Our findings suggest higher diagnostic usefulness of serum IL-6 than CRP, CEA, and CA 19-9 in the diagnosis and prognosis of patients with pancreatic cancer and in the differentiation with chronic pancreatitis. (Mroczko et al 2010)

NF-kappaB – In a xenograft mouse model of human pancreatic cancer, CDF treatment significantly inhibited tumor growth, which was associated with decreased NF-κB DNA binding activity, COX-2, and miR-21 expression, and increased PTEN and miR-200 expression in tumor remnants. (Bao et al 2011)

p53 – The detection of mutations in tumor-suppressor genes is associated with approximately half of human cancers, including colorectal, breast, bladder, esophageal, liver, lung, ovarian and brain (p53) and pancreas cancers; leukemias; and male germ cell cancers (DCC). Laboratory Tests and Diagnostic Procedures, p. 361 (2008)

Survivin – The expression of survivin may be associated with the route of metastasis and the sensitivity to chemotherapy for patients with pancreatic cancer. Lee et al 2005 investigated 49 cases of pancreatic cancer and found that 93.9% of them were positive for survivin expression. In patients with positive expression of survivin, perineural invasion was more common; while in patients with negative expression of survivin, venous invasion seemed more common. These findings suggest that survivin may be associated with perineural or venous invasion, which indicate the metastatic route. However, the reason for the relationship between survivin expression and invasion mode is not clear. Among these patients, 14 received epirubicin, cisplatin and 5-FU combination chemotherapy. Patients with lower expression of survivin were more sensitive to the chemotherapeutic protocol. The results suggest that survivin may be used as a potential predictive marker in chemotherapy. (Liu & Wang 2011)

TOPO IIa  – Significant proportion of the tumors in pancreatic ductal adenocarcinomas showed Topo IIa overexpression (32/50 or 64%). Gene amplification and deletion were detected in 9 and 4 cases, respectively, associated with protein overexpression. Aneuploidy regarding chromosome 17 was observed in 19/50 tumors and correlated with poor survival rate (Cox regression test: p = 0.001). Topo IIa protein expression was strongly correlated with stage (p = 0.021) and grade (p = 0.034). (Tsiambas et al 2007)

VEGF – Because pancreatic cancer has been found to have a profoundly hypoxic environment with high vascular in-growth, several agents have been developed to target the angiogenesis process. Major emphasis has been placed on anti- vascular endothelial growth factor (VEGF) models and the epidermal growth factor receptor (EGFR) signaling pathway. Over the past several years, a number of phase II and phase III trials have combined gemcitabine with these novel treatments, with the hope of prolonging survival in patients with pancreatic cancer.  (Assifi & Hines 2011)

References

Bagchi, Debasis & Harry G. Preuss, Phytopharmaceuticals in Cancer Chemoprevention, CRC Press, Boca Raton, 2005

Beckett, Geoffrey, Simon Walker, Peter Rae & Peter Ashby, Lecture Notes – Clinical Biochemistry, 8th edition, Wiley-Blackwell, Oxford,  2010

Boik, John, Natural Compounds in Cancer Therapy, Oregon Medical Press, Princeton, MN, 2001

Boik, John, Cancer & Natural Medicine, A Textbook of Basic Science and Clinical Research, Oregon Medical Press, Princeton, MN, 1996

Chernecky, Cynthia C, and Barbara J. Berger, Laboratory Tests and Diagnostic Procedures, Saunders, St. Louis, 2008

Davis, Cindy D, Nancy Emenaker and John Milner, “Cellular Proliferation, Apoptosis and Angiogenesis: Molecular Targets for Nutritional Preemption of Cancer, Seminars in Oncology, Vol 37, No. 3, June 2010, pp 243-257

Gullet, Norleena P, Ruhul Arnin, Soley Bayraktar, et al, “Cancer Prevention With Natural Compounds”, Seminars in Oncology, Vol 37, No 3, June 2010, pp 258-281

Heber, David, Editor-in –Chief, Nutritional Oncology, Second Edition, Academic Press, London, 2006

McKenna, Dennis J., PhD,  Kenneth Hones & Kerry Hughes, Botanical Medicines, The Desk Reference for Major Herbal Supplements, Second Edition, The Haworth Herbal Press, New York, 2002

Mills, Simon and Kerry Bone, Principles and Practice of Phytotherapy, Churchill Livingstone, Edinburgh, 2000

Neal, Michael J., Medical Pharmacology at a Glance, Sixth edition, Wiley-Blackwell, Oxford, 2009

Stargrove, Mitchell, Jonathan Treasure & Dwight L. McKee, Herb, Nutrient, and Drug Interactions, Mosby Elsevier, St. Louis,  2008

Weiss, Rudolf, MD & Volker Fintelmann, MF, Herbal Medicine, Thieme, New York, 2000

Yance, Donald, “Donald Yance’s Eclectic Triphasic Medical System (ETMS): An Integrative Wholistic Approach to Treating and Preventing Cancer”, (Monograph) 2010

Yance, Donald, Herbal Medicine, Healing & Cancer, Keats Publishing, Lincolnwood (Chicago) IL, 1999

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Compassionate Acupuncture and Healing Arts, providing craniosacral acupuncture, herbal and nutritional medicine in Durham, North Carolina. Phone number 919-309-7753.

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