THE JOURNAL OF ALTERNATIVE AND COMPLEMENTARY MEDICINE Volume 16, Number 4, 2010, pp. 497–500 ª Mary Ann Liebert, Inc. DOI: 10.1089=acm.2008.0237
Shrinkage of Gastric Cancer in an Elderly Patient Who Received Rhus verniciflua Stokes Extract Sang-Hun Lee, O.M.D., Ph.D.,1 Won-Cheol Choi, O.M.D., Ph.D.,2 Kyung-Suk Kim, O.M.D., Ph.D.,1 Jae-Woo Park, O.M.D., Ph.D.,1 Sang-Hoon Lee, O.M.D., Ph.D.,3 and Seong-Woo Yoon, O.M.D., Ph.D.1
Abstract
Background: Many studies have suggested that the flavonoids from Rhus verniciflua Stokes (RVS) are anticancer agents, but a few clinical studies have reported on this topic. Patient and method: We present here the case of a female patient (82 years old) with an adenocarcinoma of the stomach that was first diagnosed via an abdomen computed tomography (CT) scan and endoscopic biopsy. Any conventional therapy such as surgical resection was not performed because of her advanced age. She wanted to receive alternative care, and so she was exclusively treated with standardized RVS extract. Course of therapy and results: Daily therapy with 900 mg of orally administered RVS extract was initiated on September 25, 2006. Five (5) months later, the gastroscopy and abdomen CT scan showed a marked decrease in the polypoid mass at the mid body and a slight decrease in the flat elevated lesion at the prepyloric antrum, as compared to tumor sizes on the first gastroscopy and abdomen CT scan. She is alive and doing well at the present time (April 2009). Conclusions: We suggest that RVS extract could be a candidate for a natural agent that induces selective apoptosis and inhibits cell growth in gastric adenocarcinoma.
whose gastric cancer decreased in size when she took a standardized extract from RVS as her exclusive therapy.
Introduction
G
astric cancer is the leading cause of cancer death worldwide, and it is the most prevalent malignancy in Korea.1 The extending lifespan of the general population has caused an increasing incidence of gastric cancer in people over 70 years of age.2 Although complete surgical removal of the gastric tumor is the only curative treatment, making the decision to perform surgery is difficult for elderly patients because of their reduced functional reserve of various organs and their many comorbidities.3 Patients over 80 years are considered to be at high risk for postoperative complications and death that are unrelated to the carcinoma.4 Rhus verniciflua Stokes (RVS) of the Anacardiaceae family has traditionally been used in East Asian countries for treating various stomach diseases, including tumor.5 RVS acts against malignant tumors because of its property of breaking up blood stasis and purging hardness, as based on traditional medicine theory.6 Many experimental studies have also reported that RVS has antiproliferative and apoptotic activities in human cancer cell lines, including gastric carcinoma.7–10 We report here on an elderly patient
Patient and Method Patient We describe here an 82-year-old female who had been diagnosed with gastric cancer via an abdominal computed tomography (CT) scan on September 2, 2006. The CT detected a gastric mass in the gastric antrum and the small gastrohepatic lymph nodes without metastasis to any other organs (Fig. 1A). She had been continuously taking antihypertensive medication for 10 years, and her past medical history included osteoarthritis and allergic rhinitis. Two (2) cases of gastric cancer in her family were reported. For further evaluation, a gastroscopy on October 9, 2006 revealed a polypoid gastric mass approximately 25 mm in diameter at the middle body portion of the lesser curvature and a flat elevated lesion 50 mm in diameter at the prepyloric antrum (Fig. 2A, B). The endoscopic biopsy confirmed well-differentiated adenocarcinoma with a mutation in p53 that showed high nuclear activity of more than 80% (Fig. 3A, B). Surgical removal was recommended, but this could not be
1 Department of Internal Medicine, 2Department of Clinical Oncology, and 3Department of Acupuncture and Moxibustion, Mu Integrative Cancer Center, East–West Neo Medical Center, College of Oriental Medicine, Kyung Hee University, Seoul, Republic of Korea.
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FIG. 1. An abdominal computed tomography (CT) scan dated September 2, 2006 revealed a polypoid mass in the gastric antrum (A); an abdominal CT scan dated February 22, 2007 showed that the gastric mass could hardly be seen (B). done because of her advanced age and the concerns about the quality of life after gastrectomy. Standardized extract of RVS The clinical application of RVS has been limited because RVS, like poison ivy and many other plants of the Anacardiaceae family, causes contact dermatitis on sensitive individuals.11 An allergenic component, urushiol, which is a mixture of several derivatives of catechol, should be removed from the RVS before RVS is used pharmaceutically. A standardized extract of urushiol-free RVS was manufactured according to the method disclosed by a Korean patent (no. 0504160). Ten (10)-year-old RVS stalks and the bark, which were grown in Wonju, Republic of Korea, were processed to sawdust and then dried to less than 5% water content. They were roasted in an iron pot at 2408C for 50 minutes, and extracted with a 10-fold volume of water at 908C–958C for 6 hours. The extract was concentrated in a vacuum evaporator and then it was dried to a dark brown powder, then the final product was meshed through a screen. The yield of the final extract was 3.3% (wt=wt). The major compounds are flavonoids such as fustin and fisetin according to high performance liquid chromatography, while sulfuretin and butein were also detected as minor components. There is significant variation in the composition of the final product due to the presence of some deviation resulting from the age and harvest time of the trees, the growing areas, the parts to be harvested, etc. The quality of the RVS extract was tested and controlled according to the quality standards of the Korea Food & Drug Administration and our hospital’s standards (fustin > 13.0%, fisetin > 2.0%, urushiol not detected). Treatment course Daily therapy with 900 mg of orally administered RVS extract was initiated on September 25, 2006. Five (5) months later, the gastroscopy and abdominal CT scans demonstrated that the polypoid mass in the mid body had markedly de-
creased and the flat elevated lesion in the prepyloric antrum had shrunk slightly, although the gastrohepatic lymph nodes were not changed (Figs. 1B, 2C, D). The biochemical parameters associated with liver and renal function were within the normal range, and no significant side-effects from her RVS treatment have been observed. She maintains a good performance status at the present time (April 2009). She does not want to receive follow-up evaluation for her tumor, including CT scans or gastroscopy. Discussion Gastric cancer in elderly patients has unique characteristics, including a high frequency of differentiated tumors, blood vessel invasion, and hematogenous recurrence.2 Early gastric cancer generally progresses to the advanced stage with time, and it will usually lead to death from gastric cancer if left untreated.12 In this case, an 82-year-old female patient with gastric cancer showed a markedly decreased size of her polypoid mass, from 25 mm in diameter to a bulging state, after treatment with RVS extract for 5 months. Although the stage could not be exactly determined without an endoscopic ultrasound scan, the tumor contracted and a good performance status was achieved with the oral administration of RVS extract. She received no other systemic treatments or chemotherapy before or after taking RVS extract. Therefore, it stands to reason that the reduction of the tumor size was indeed induced by RVS. RVS has been experimentally reported to have selective growth inhibition and apoptosis-inducing effects. An ethanol extract of RVS in vitro was shown to induce apoptosis through the intrinsic pathway and G1 cell cycle arrest in human AGS gastric cancer cells, but not in normal cells.8,13 A purified flavonoid fraction prepared from RVS was also observed to be capable of inducing apoptosis in human osteosarcoma cells by activating p53, which in turn causes mitochondrial stress leading to the release of apoptosisinducing factor and endonuclease G into the nucleus.14 The butein (3,4,2’,4’-tetrahydroxychalone) component of the flavonoid fraction from RVS was previously shown to interfere
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FIG. 2. A gastroscopy dated October 9, 2006 revealed a polypoid mass that was approximately 25 mm in diameter at the middle body portion at the lesser curvature (A) and a flat elevated lesion 50 mm in diameter at the prepyloric antrum (B). A gastroscopy scan dated February 22, 2007 showed that the size of the polypoid mass decreased to a bulging level (C) and the flat elevated lesion was reduced in comparison with the previous image (D).
FIG. 3. A gastric middle body biopsy specimen stained with hematoxylin and eosin showed well-differentiated adenocarcinoma (A). Anti-p53 immunohistochemical staining demonstrates more than 80% of nuclear activity in the mutation (B). with the interaction between fibroblasts and breast cancer cells in vitro.15 The aqueous extract of urushiol-free RVS was demonstrated in vivo to suppress the tumor volume in a xenograft mouse model system that used A549 non-smallcell lung cancer cells and Lewis lung cancer cells via inhibiting the proliferation and migratory activity of vascular endothelial growth factor.16 It was recently reported that an aqueous extract of urushiol-free RVS potentiated the cisplatin-induced antitumor activity in CT-26 murine colon carcinoma in vivo along with having antioxidant activity to reduce the cisplatin-induced cytotoxicity.17 Therefore, we hope that this case would stimulate further investigation into the effectiveness and tolerability of RVS for the treatment of gastric tumors in clinical practice, though it
should not be generalized for use in all cases. Follow-up monitoring and further clinical trials with a large population are required to investigate its efficacy and safety. We suggest that RVS could be a candidate natural compound for inducing selective apoptosis and inhibiting cell growth in gastric adenocarcinoma. Acknowledgments We would like to thank our patient, who consented to having her case presented and published. Disclosure Statement No competing financial interests exist.
500 References 1. Lee HJ, Yang HK, Ahn YO. Gastric cancer in Korea. Gastric Cancer 2002;5:177–182. 2. Saito H, Osaki T, Murakami D, et al. Effect of age on prognosis in patients with gastric cancer. ANZ J Surg 2006; 76:458–461. 3. Pisanu A, Montisci A, Piu S, Uccheddu A. Curative surgery for gastric cancer in the elderly: Treatment decisions, surgical morbidity, mortality, prognosis and quality of life. Tumori 2007;93:478–484. 4. Eguchi T, Fujii M, Takayama T. Mortality for gastric cancer in elderly patients. J Surg Oncol 2003;84:132–136. 5. Kim TJ. Korea Resource Plants, vol. II. Seoul, Korea: Seoul University Press, 1996:292–297. 6. Bensky D, Gamble A, Kaptchuk T. Chinese Herbal Medicine: Materia Medica. Seattle, WA: Eastland Press, 1993:293. 7. Jang HS, Kook SH, Son YO, et al. Flavonoids purified from Rhus verniciflua Stokes actively inhibit cell growth and induce apoptosis in human osteosarcoma cells. Biochim Biophys Acta 2005;1726:309–316. 8. Kim JH, Kim HP, Jung CH, et al. Inhibition of cell cycle progression via p27Kip1 upregulation and apoptosis induction by an ethanol extract of Rhus verniciflua Stokes in AGS gastric cancer cells. Int J Mol Med 2006;18:201–208. 9. Lee JC, Lee KY, Kim J, et al. Extract from Rhus verniciflua Stokes is capable of inhibiting the growth of human lymphoma cells. Food Chem Toxicol 2004;42:1383–1388. 10. Son YO, Lee KY, Lee JC, et al. Selective antiproliferative and apoptotic effects of flavonoids purified from Rhus verniciflua Stokes on normal versus transformed hepatic cell lines. Toxicol Lett 2005;155:115–125. 11. Lovell CR. Poison oak. In: Plants and the Skin, 1st ed. Oxford: Blackwell Scientific Publications, 1993:106–110. 12. Tsukuma H, Oshima A, Narahara H, Morii T. Natural history of early gastric cancer: A non-concurrent, long term, follow up study. Gut 2000;47:618–621.
LEE ET AL. 13. Kim JH, Go HY, Jin DH, et al. Inhibition of the PI3KAkt=PKB survival pathway enhanced an ethanol extract of Rhus verniciflua Stokes-induced apoptosis via a mitochondrial pathway in AGS gastric cancer cell lines. Cancer Lett 2008;265:197–205. 14. Kook SH, Son YO, Chung SW, et al. Caspase–independent death of human osteosarcoma cells by flavonoids is driven by p53-mediated mitochondrial stress and nuclear translocation of AIF and endonuclease G. Apoptosis 2007;12:1289– 1298. 15. Samoszuk M, Tan J, Chorn G. The chalcone butein from Rhus verniciflua Stokes inhibits clonogenic growth of human breast cancer cells co-cultured with fibroblasts. BMC Complement Altern Med 2005;9:5. 16. Choi WC, Lee JH, Lee EO, et al. Study on antiangiogenic and antitumor activities of processed Rhus verniciflua Stokes extract. Korean J Oriental Physiol Pathol 2006;20:825– 829. 17. Lee JH, Lee HJ, Lee HJ, et al. Rhus verniciflua Stokes prevents cisplatin-induced cytotoxicity and reactive oxygen species production in MDCK-I renal cells and intact mice. Phytomedicine 2009;16:188–197.
Address correspondence to: Seong-Woo Yoon, O.M.D., Ph.D. Department of Internal Medicine Mu Integrative Cancer Center East–West Neo Medical Center College of Oriental Medicine Kyung Hee University 149 Sangil-dong, Gangdong-Ku Seoul, #134-727 Republic of Korea E-mail:
[email protected]
