Anti-tumor Activity of Nuvastatic^TM (C5OSEW5050ESA) of Orthosiphon stamineus and Rosmarinic Acid in An Athymic Nude Mice Model of Breast Cancer

Ashwaq Hamid Salem Yehya^a,*, Majed Ahmed Al-Mansoub^b, Fouad Saleih Resq Al-Suede^a, Siti Balkees Binti STN Hameed Sultan^a, Muhammad Asyraf Abduraman^a, Noor Amanina Azmi^c, Mufda jameel abedalhadi alrawashdeh^d, Seyedeh Fatemeh Jafari^e, Amin Malik Shah Abdul Majid^a,f

Abstract

The current treatment strategies for metastatic breast cancer depend on the cancer subtype by palliating symptoms and prolonging life. However, triple-negative breast cancers have no targeted treatment available. Orthosiphon stamineus (O.s) is a traditional folk medicine plant used in South East Asia to treat many diseases. The aim of this study is to evaluate the anti-tumor activity of O.s extract formulation (ID: C5EOSEW5050ESA trademarked as Nuvastatic^TM) and its major component, rosmarinic acid in a breast in vivo tumor xenograft model. Human triple-negative breast cancer cells were transplanted into the mammary fat pad of 20 athymic nude mice. Fourteen days post-injection, mice were randomly assigned to four groups. C5EOSEW5050ESA (200 and 400 mg/kg/day) and rosmarinic acid (32 mg/kg/day) were administered orally. The body weight and tumor size were measured twice a week. Histopathological analyses of tumor tissues were conducted. Tumor necrosis and tumor growth were determined by hematoxylin and eosin staining. A significant reduction in tumor size and growth was found in all treatment groups. No significant difference between C5EOSEW5050ESA at 200 mg/kg and rosmarinic acid in the reduction of tumor size and necrosis. However, a more significant reduction  was found in tumor growth and necrosis with 400 mg/kg of C5EOSEW5050ESA treatment as compared to other treatments. These results highlighted the anti-tumor activity of C5EOSEW5050ESA in reducing breast tumor growth in mice compared to the lower dose of C5EOSEW5050ESA and rosmarinic acid. This study provides valuable insights into using C5EOSEW5050ESA as a treatment to target triple-negative breast cancers in vivo.

Keywords: Breast cancer; Orthosiphon stamineus; C5EOSEW5050ESA; Rosmarinic acid; Nuvastatic^TM; Medicinal plant; Anti-tumor.

References

Abdelwahab, S.I., et al., Antiapoptotic and Antioxidant Properties of Orthosiphon stamineus Benth (Cat's Whiskers): Intervention in the Bcl-2-Mediated Apoptotic Pathway. Evid Based Complement Alternat Med, 2011. 2011: p. 156765.

Ahamed, M.B.K., et al., Orthosiphon stamineus leaf extract can prevent the development of colorectal and breast cancer in vivo. Vol. 3. 2010.

Al-Suede, F., et al., Immunomodulatory and antiangiogenic mechanisms of polymolecular botanical drug extract C5OSEW5050ESA OS derived from Orthosiphon stamineus. Journal of Angiotherapy, 2021. 5.

Al-Suede, F., et al., Marked antitumor activity of cat's whiskers tea (Orthosiphon stamineus) extract in orthotopic model of human colon tumor in nude mice. Journal of Biochemical Technology, 2014. 3(5): p. 170-176.

Al-Suede, F.S.R., et al., Optimization of Cat’s Whiskers Tea (<i>Orthosiphon stamineus</i>) Using Supercritical Carbon Dioxide and Selective Chemotherapeutic Potential against Prostate Cancer Cells. Evidence-Based Complementary and Alternative Medicine, 2014. 2014: p. 396016.

Androutsopoulos, V., et al., Antiproliferative and cytostatic effects of the natural product eupatorin on MDA-MB-468 human breast cancer cells due to CYP1-mediated metabolism. Breast Cancer Research, 2008. 10(3): p. R39.

Dass, S.A., et al., Triple negative breast cancer: A review of present and future diagnostic modalities. Medicina, 2021. 57(1): p. 62.

Dong, Y., et al., Effects of sinensetin on proliferation and apoptosis of human gastric cancer AGS cells. Zhongguo Zhong yao za zhi= Zhongguo zhongyao zazhi= China journal of Chinese materia medica, 2011. 36(6): p. 790-794.

Gilchrist, K.W., et al., Tumor necrosis is a prognostic predictor for early recurrence and death in lymph node-positive breast cancer: a 10-year follow-up study of 728 Eastern Cooperative Oncology Group patients. Journal of Clinical Oncology, 1993. 11(10): p. 1929-1935.

Mohamed, E.A.H., et al., Toxicity evaluation of a standardised 50% ethanol extract of Orthosiphon stamineus. Journal of Ethnopharmacology, 2011. 133(2): p. 358-363.

Sayles, L.C., et al., Genome-informed targeted therapy for osteosarcoma. Cancer discovery, 2019. 9(1): p. 46-63.

Shafaei, A., et al., Genotoxicity, acute and subchronic toxicity studies of nano liposomes of Orthosiphon stamineus ethanolic extract in Sprague Dawley rats. BMC complementary and alternative medicine, 2015. 15(1): p. 360.

Sharmila, R. and S. Manoharan, Anti-tumor activity of rosmarinic acid in 7, 12-dimethylbenz (a) anthracene (DMBA) induced skin carcinogenesis in Swiss albino mice. 2012.

Tabana, Y.M., et al., Cat’s whiskers (Orthosiphon stamineus) tea modulates arthritis pathogenesis via the angiogenesis and inflammatory cascade. BMC Complementary and Alternative Medicine, 2016. 16(1): p. 480.

Waks, A.G. and E.P. Winer, Breast cancer treatment: a review. Jama, 2019. 321(3): p. 288-300.

Yehya, A., et al., Angiogenesis: Managing the culprits behind tumorigenesis and metastasis. Medicina, 2018. 54(1): p. 8.

Yehya, A.H., et al., Broad spectrum targeting of tumor vasculature by medicinal plants: An updated review. Journal of Herbal Medicine, 2017. 169(13)

Yehya, A.H., et al., Complementary effects of Orthosiphon stamineus standardized ethanolic extract and rosmarinic acid in combination with gemcitabine on pancreatic cancer. Biomedical Journal, 2020. 2020. 44(6): p.694-708.

Yehya, A.H., et al., Toxicological studies of Orthosiphon stamineus (Misai Kucing) standardized ethanol extract in combination with gemcitabine in athymic nude mice model. Journal of advanced research, 2019. 15: p. 59-68.