Thymoquinone Augments Chemotherapy Treatment of Pancreatic Cancer

Study explores effects of gemcitabine and oxaliplatin on pancreatic cancer cells through in vitro and in vivo experiments.

By Jacob Schor, ND, FABNO

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Reference

Banerjee S, Kaseb AO, Wang Z, et al. Antitumor activity of gemcitabine and oxaliplatin is augmented by thymoquinone in pancreatic cancer. Cancer Res. 2009;69(13):5575-5583.
 

Design

A series of in vitro and in vivo experiments comparing effects of gemcitabine and oxaliplatin on pancreatic cancer cells, some of which were pretreated with thymoquinone.
 

Methods

This study consists of two parts. The first part was composed of a series of in vitro experiments on human pancreatic cancer cell lines and healthy human pancreatic ductal epithelial cells that served as controls. These cell lines were used to examine the effect of thymoquinone alone and in combination with the chemotherapy drugs gemcitabine and oxaliplatin. The second part of the study was an in vivo experiment in which human pancreatic cancer was implanted into mice, and similar comparisons were made regarding the effectiveness of these agents alone and in combination with thymoquinone.
 

Results

The following effects were noted from the in vitro experiments with pancreatic cancer cell cultures:
  1. Thymoquinone alone inhibited cancer cell viability in almost all pancreatic cancer cell lines tested, inhibiting it up to 70%, but caused only minimal effect on the healthy cells used as controls.
  2. Thymoquinone inhibited the anti-apoptotic molecules Bcl-2 and Bcl-xL and induced the pro-apoptotic molecule Bax. Thymoquinone also inhibited other anti-apoptotic molecules including Mcl-a, survivin, and XIAP.
  3. Thymoquinone inhibited cyclo-oxygenase-2 (COX-2) expression and PGE-2 accumulation in a dose-dependent manner. The COX-2 enzyme is overexpressed in pancreatic cancer and is involved in inhibition of apoptosis, potentiation of cell growth, and angiogenesis and so is considered a target for drug development.
  4. Thymoquinone inhibits activation of nuclear factor-kappaB (NF-kappa B) in a dose-dependent manner.
  5. Thymoquinone sensitized pancreatic cancer cells to chemotherapy drugs. Cancer cells were either treated with thymoquinone (25 umol/L for 48 hours) followed by a 24-hour incubation with either gemcitabine or oxaliplatin. The pretreatment with thymoquinone alone or treatment with one of the chemotherapy drugs alone caused a 15–50% decrease in viable pancreatic cancer cells. However combining thymoquinone pretreatment with either of the chemotherapy drugs resulted in a 65–80% loss of viable cancer cells (P<0.001) through increased apoptosis.
  6. Treatment with either chemotherapy drug stimulated NF-kappa B, but pretreatment with thymoquinone prevented this increase.
In a personal correspondence with Sanjeev Banerjee he described the following results from the in vivo portion of this study:
  • Administration of thymoquinone alone caused a 38% reduction in tumor weight.
  • Gemcitabine or oxaliplatin alone caused 66% and 58% reductions in tumor weight.
  • Combining thymoquinone with either of the chemotherapy drugs caused a statistically significant further decrease in tumor weight.
  • In the thymoquinone combined with gemcitabine group, the reduction in tumor weight was 85%, whereas in the oxaliplatin and thymoqhinone group tumor weight reduction was 76%.
 

Key Findings

Thymoquinone exposure resulted in 60–80% growth inhibition compared with 15–25% when gemcitabine or oxaliplatin was used alone. Thymoquinone potentiated the killing of pancreatic cancer cells by chemotherapeutic agents by down-regulation of NF-kappa B, Bcl-2 family, and NF-kappa B–dependent antiapoptotic signaling.
 

Practice Implications

The US Food and Drug Administration cleared Eli Lilly’s drug gemcitabine (Gemzar) for use in treating advancer pancreatic cancer (PC) in 1996. Though it is still frequently used for this purpose, its effectiveness is limited, so various combinations of gemcitabine with other chemotherapy drugs have been studied, with no clinically significant increase in patient survival.1 Radiotherapy, in addition to chemotherapy drugs, is currently under study but has yet to show benefit in prolonging survival.2 There is ongoing interest in natural agents, in particular agents that may down-regulate NF-Kappa B, which is thought to be a major mechanism contributing to pancreatic cancer’s chemoresistance. This paper suggests one possible but rarely used agent we might incorporate into our practices.
 
Thymoquinone is extracted from the seed of Nigella sativa, often referred to as black cumin seeds, though these are not cumin seeds at all. This plant is obscure in western botanical literature: Its name has no direct translation into English. Yet these seeds have a long and illustrious history of medical use in the Muslim world. The prophet Mohammad is quoted as saying that the black seed can heal every disease—except death.
 
Nigella seeds are considered a panacea in the Middle East and Southeast Asia and are used to treat a range of conditions including asthma, bronchitis, rheumatism and related inflammatory diseases; to increase milk production in nursing mothers; to promote digestion; and to fight parasitic infections. Nigella oil has been used to treat skin conditions such as eczema and boils and to treat cold symptoms.
 
This is not the first paper on Nigella to suggest a significant potential in treating cancer. A 1998 paper in Cancer Research reported on the effect of both crude extracts and refined oils obtained from Nigella seed on human cancer cells. Although the crude gum had no effect, the purified extract thymoquinone (TQ) and dithymoquinone (DIM) both were effective in killing the multiple cancer cell lines they were tested on, including multi-drug resistant (MDR) cell lines insensitive to doxorubicin and etoposide.3
 
In 2005, Irish researchers reported that extracts of Nigella sativa caused cancer cell death by apoptosis and necrosis in a dose- and time-dependent manner on cell lines from lung cancer, cancer of the larynx, colon cancer, and pancreatic cancer.4
 
Whole and ground Nigella seeds along with oil extracts are often sold in markets catering to Muslim immigrants. Standardized extracts with reported thymoquinone concentrations are not yet readily available for professional use, although some distributors are considering marketing them. The data reported in this recent paper may provide the impetus needed.
Nigella sativa is one of several natural agents that increase chemotherapy action against pancreatic cancer.
 
Nigella sativa is one of several natural agents that increase chemotherapy action against pancreatic cancer. Recent papers report similar potentiating effects may be triggered by gossypol, genistein, curcumin, green tea, cruciferous vegetables, gamma-linolenic acid, and resveratrol.5,6,7,8,9,10,11
 
For more research involving integrative oncology, click here.

About the Author

Jacob Schor ND, FABNO, is a graduate of National College of Naturopathic Medicine, Portland, Oregon, and now practices in Denver, Colorado. He served as president to the Colorado Association of Naturopathic Physicians and is on the board of directors of the Oncology Association of Naturopathic Physicians. He is recognized as a fellow by the American Board of Naturopathic Oncology. He serves on the editorial board for the International Journal of Naturopathic Medicine, Naturopathic Doctor News and Review (NDNR), and Integrative Medicine: A Clinician's Journal. In 2008, he was awarded the Vis Award by the American Association of Naturopathic Physicians. His writing appears regularly in NDNR, the Townsend Letter, and Natural Medicine Journal, where he is the Abstracts & Commentary editor.

References

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  2. Huguet F. [Is there still a place for radiotherapy for the treatment of pancreatic cancers?][Article in French]. Presse Med. 2009. Epub ahead of print.
  3. Worthen DR, Ghosheh OA, Crooks PA. The in vitro anti-tumor activity of some crude and purified components of blackseed, Nigella sativa L. Anticancer Res. 1998;18(3A):1527-1532.
  4. Rooney S, Ryan MF. Effects of alpha-hederin and thymoquinone, constituents of Nigella sativa, on human cancer cell lines. Anticancer Res. 2005;25(3B):2199-2204.
  5. Banerjee S, Choi M, Aboukameel A, et al. Preclinical studies of apogossypolone, a novel pan inhibitor of Bcl-2 and Mcl-1, synergistically potentiates cytotoxic effect of gemcitabine in pancreatic cancer cells. Pancreas. 2009. Epub ahead of print.
  6. Banerjee S, Zhang Y, Ali S, et al. Molecular evidence for increased antitumor activity of gemcitabine by genistein in vitro and in vivo using an orthotopic model of pancreatic cancer. Cancer Res. 2005;65(19):9064-9072.
  7. Kunnumakkara AB, Guha S, Krishnan S, Diagaradjane P, Gelovani J, Aggarwal BB. Curcumin potentiates antitumor activity of gemcitabine in an orthotopic model of pancreatic cancer through suppression of proliferation, angiogenesis, and inhibition of nuclear factor-kappaB-regulated gene products. Cancer Res. 2007;67(8):3853-3861.
  8. Lang M, Henson R, Braconi C, Patel T. Epigallocatechin-gallate modulates chemotherapy-induced apoptosis in human cholangiocarcinoma cells. Liver Int. 2009;29(5):670-677.
  9. Banerjee S, Wang Z, Kong D, Sarkar FH. 3,3'-Diindolylmethane enhances chemosensitivity of multiple chemotherapeutic agents in pancreatic cancer. Cancer Res. 2009;69(13):5592-5600.
  10. Whitehouse PA, Cooper AJ, Johnson CD. Synergistic activity of gamma-linolenic acid and cytotoxic drugs against pancreatic adenocarcinoma cell lines. Pancreatology. 2003;3(5):367-373; discussion 373-374.
  11. Harikumar KB, Kunnumakkara AB, Sethi G, et al. Resveratrol, a multi-targeted agent, can enhance antitumor activity of gemcitabine in vitro and in orthotopic mouse model of human pancreatic cancer. Int J Cancer. 2009. Epub ahead of print.