Investigation Of Anti-Tumour Activity Of Orthosiphon Stamineus On Human Oral Squamous Cell Carcinoma

Shah kamal Bin Jamal Din^a, Fouad Saleih Resq Al-Suede^b,c*,Farahnaz Amini^d, Aman Shah Abdul Majid^e, JackTan Chun Keat^d, Amin Malik Shah Abdul Majid^f .

The potential of Nuvastatic in the treatment of oral squamous cell carcinoma.

Abstract

Introduction: Oral Cancer contributes to 1.11% of total deaths in Malaysia, with 1,865 cases reported in 2020. In this study, the standardized extract of NuvastaticTM (C5OSEW5050ESA) showed antitumor activity in oral cell carcinoma in vitro and in vivo. The active ingredient of NuvastaticTM is derived from a standardized extract of Orthosiphon stamineus based on 6% rosmarinic acid. The present study was conducted to evaluate the anticancer potential of C5OSEW5050ESA OS against human oral squamous cell carcinoma (CAL27) ectopically implanted into Nu/Nu nude mice. Methods: The cytotoxicity of C5OSEW5050ESA OS against human oral squamous cell carcinoma CAL27) was evaluated using the MTT assay. The antitumor activity of C5OSEW5050ESA OS was performed by ectopically implanting CAL27 cells into athymic NCR Nu/Nu nude mice. The diseased animals were treated with 200 and 400mg/kg C5OSEW5050ESA OS daily for 3 weeks. Result: The study showed that C5OSEW5050ESA was weakly cytotoxic against CAL27 with an IC50 of 899.2 µg/ml. At a dose of 200 and 400 mg/kg, compound C5OSEW5050ESA showed significant anti-tumor effect in xenograft cancer model. C5OSEW5050ESA showed a dose-dependent suppression of oral cancer growth with 74.1.1±1.1 and 81.7±2.1% compared to the negative control group at 200 mg/kg and 400 mg/kg, respectively. In addition, the cancer growth of the positive control (imatinib) treated animals showed that the size of cancer growth reduced significantly with 52.4±2 compared to the negative control (untreated) group. Conclusion: The result of this study highlights the potential of NuvastaticTM in the treatment of oral squamous cell carcinoma.

Keywords: Oral squamous cell carcinoma (OSCC), C5OSEW5050ESA, Orthosiphon Stamineus, xenograft tumor model, botanical drug.

References

Ahamed, M. B. K., Aisha, A. F., Nassar, Z. D., Siddiqui, J. M., Ismail, Z., Omari, S. M. S., & Majid, A. A. (2012). Cat's whiskers tea (Orthosiphon stamineus) extract inhibits growth of colon tumor in nude mice and angiogenesis in endothelial cells via suppressing VEGFR phosphorylation. Nutrition and Cancer, 64(1), 89-99.

Ahmad, W. M. A. W., Harun, M. H., Aleng, N. A., Ghazali, F. M. M., Rohim, R. A. A., & Akbar, N. A. N. (2021). Oral Squamous Cell Carcinomas: A Statistical Study to Determine the Potential Prognostics Factors that Affect the Tumor Size. International Medical Journal, 28(3).

Almoustafa, H. A., Alshawsh, M. A., Al-Suede, F. S. R., Alshehade, S. A., Abdul Majid, A. M. S., & Chik, Z. (2023). The Chemotherapeutic Efficacy of Hyaluronic Acid Coated Polymeric Nanoparticles against Breast Cancer Metastasis in Female NCr-Nu/Nu Nude Mice. Polymers, 15(2), 284.

Al-Salahi, O. S. A., Kit-Lam, C., Majid, A. M. S. A., Al-Suede, F. S. R., Saghir, S. A. M., Abdullah, W. Z., ... & Yusoff, N. M. (2013). Anti-angiogenic quassinoid-rich fraction from Eurycoma longifolia modulates endothelial cell function. Microvascular research, 90, 30-39.

Alshehade, S. A., Al Zarzour, R. H., Mathai, M., Giribabu, N., Seyedan, A., Kaur, G., ... & Alshawsh, M. A. (2023). Orthosiphon aristatus (Blume) Miq Alleviates Non-Alcoholic Fatty Liver Disease via Antioxidant Activities in C57BL/6 Obese Mice and Palmitic–Oleic Acid-Induced Steatosis in HepG2 Cells. Pharmaceuticals, 16(1), 109.

Al-Suede, F. S. R., Farsi, E., Ahamed, M. K. B., Ismail, Z., Majid, A. S. A., & Majid, A. M. S. A. (2014). Marked antitumor activity of cat’s whiskers tea (Orthosiphon stamineus) extract in orthotopic model of human colon tumor in nude mice. J Biochem Technol, 3(5), S170-6.

Al-Suede, F. S. R., Khadeer Ahamed, M. B., Abdul Majid, A. S., Baharetha, H. M., Hassan, L. E., Kadir, M. O. A., ... & Abdul Majid, A. (2014). Optimization of cat’s whiskers tea (orthosiphon stamineus) using supercritical carbon dioxide and selective chemotherapeutic potential against prostate cancer cells. Evidence-Based Complementary and Alternative Medicine, 2014.

Al-Suede, F. S. R., Saghir, S. A. M., Oon, C. E., & Abdul Majid, A. M. S. (2021). Immunomodulatory and Antiangiogenic Mechanisms of Polymolecular Botanical Drug Extract C5OSEW5050ESA OS Derived from Orthosiphon Stamineus. J. Angiotherapy, 5(194), 10-25163.

Albuquerque, R., López-López, J., Marí-Roig, A., Jané-Salas, E., Roselló-Llabrés, X., & Santos, J. R. (2011). Oral tongue squamous cell carcinoma (OTSCC): alcohol and tobacco consumption versus non-consumption. A study in a Portuguese population. Brazilian dental journal, 22, 517-521.

Arrangoiz, R., Cordera, F., Caba, D., Moreno, E., de León, E. L., & Muñoz, M. (2018). Oral tongue cancer: Literature review and current management. Cancer Rep Rev, 2(3), 1-9.

Babiker, A. Y., Almatroodi, S. A., Almatroudi, A., Alrumaihi, F., Abdalaziz, M. S., Alsahli, M. A., & Husain Rahmani, A. (2020). Clinicopathological significance of VEGF and pAkt expressions in oral squamous cell carcinoma. All Life, 13(1), 507-515.

Choi, S., & Myers, J. N. (2008). Molecular pathogenesis of oral squamous cell carcinoma: implications for therapy. Journal of dental research, 87(1), 14-32.

Close, L. G., Brown, P. M., Vuitch, M. F., Reisch, J., & Schaefer, S. D. (1989). Microvascular invasion and survival in cancer of the oral cavity and oropharynx. Archives of otolaryngology–head & neck surgery, 115(11), 1304-1309.

EG, C. V., JV, B. S., Gavalda, C., & EF, T. C. (2001). Retinoids: application in premalignant lesions and oral cancer. Medicina Oral: Organo Oficial de la Sociedad Espanola de Medicina Oral y de la Academia Iberoamericana de Patologia y Medicina Bucal, 6(2), 114-123.

Demain, A. L., & Vaishnav, P. (2011). Natural products for cancer chemotherapy. Microbial biotechnology, 4(6), 687-699.

Dhanuthai, K., Rojanawatsirivej, S., Thosaporn, W., Kintarak, S., Subarnbhesaj, A., Darling, M., ... & Shakib, P. A. (2018). Oral cancer: A multicenter study. Medicina oral, patologia oral y cirugia bucal, 23(1), e23.

Diendéré, J., Zeba, A. N., Nikièma, L., Kaboré, A., Savadogo, P. W., Tougma, S. J. B., & Ouédraogo, A. (2020). Smokeless tobacco use: its prevalence and relationships with dental symptoms, nutritional status and blood pressure among rural women in Burkina Faso. BMC Public Health, 20(1), 1-9.

Bugshan, A., & Farooq, I. (2020). Oral squamous cell carcinoma: metastasis, potentially associated malignant disorders, etiology and recent advancements in diagnosis. F1000Research, 9.

Guha, N., Boffetta, P., Wünsch Filho, V., Eluf Neto, J., Shangina, O., Zaridze, D., & Brennan, P. (2007). Oral health and risk of squamous cell carcinoma of the head and neck and esophagus: results of two multicentric case-control studies. American journal of epidemiology, 166(10), 1159-1173.

Gutschner, T., & Diederichs, S. (2012). The hallmarks of cancer: a long non-coding RNA point of view. RNA biology, 9(6), 703-719.

Johnson, D. E., Burtness, B., Leemans, C. R., Lui, V. W. Y., Bauman, J. E., & Grandis, J. R. (2020). Head and neck squamous cell carcinoma. Nature reviews Disease primers, 6(1), 92.

Kramer, S., Gelber, R. D., Snow, J. B., Marcial, V. A., Lowry, L. D., Davis, L. W., & Chandler, R. (1987). Combined radiation therapy and surgery in the management of advanced head and neck cancer: final report of study 73–03 of the Radiation Therapy Oncology Group. Head & neck surgery, 10(1), 19-30.

Mosmann, T. (1983). Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. Journal of immunological methods, 65(1-2), 55-63.

Nazari, V. M., Mahmood, S., Shah, A. M., & Al-Suede, F. S. R. (2022). Suppression of melanoma growth in a murine tumour model using orthosiphon stamineus benth. Extract loaded in ethanolic phospholipid vesicles (spherosome). Current Drug Metabolism, 23(4), 317-328.

Ng, M., Abdul, A. M. S., Yee, S. M., Natesan, V., Ahamed, M. B., Ashok, G., ... & Majid, A. A. (2023). Efficacy and Safety of Nuvastatic™ in Improving Cancer-related Fatigue: A Phase II Multicenter Randomized Controlled Trial.

Parkin, D. M., Bray, F., Ferlay, J., & Pisani, P. (2005). Global cancer statistics, 2002. CA: a cancer journal for clinicians, 55(2), 74-108.

Sayles, L. C., Breese, M. R., Koehne, A. L., Leung, S. G., Lee, A. G., Liu, H. Y., ... & Sweet-Cordero, E. A. (2019). Genome-Informed Targeted Therapy for OsteosarcomaGenome-Informed Targeted Therapy for Osteosarcoma. Cancer discovery, 9(1), 46-63.

Suzuki, M., Ito, Y., Fujino, T., Abe, M., Umegaki, K., Onoue, S., & Yamada, S. (2009). Pharmacological effects of saw palmetto extract in the lower urinary tract. Acta Pharmacologica Sinica, 30(3), 271-281.

Tabana, Y. M., Al-Suede, F. S. R., Ahamed, M. B. K., Dahham, S. S., Hassan, L. E. A., Khalilpour, S., ... & Majid, A. M. S. A. (2016). Cat’s whiskers (Orthosiphon stamineus) tea modulates arthritis pathogenesis via the angiogenesis and inflammatory cascade. BMC complementary and alternative medicine, 16, 1-11.

Xia, C., Dong, X., Li, H., Cao, M., Sun, D., He, S., ... & Chen, W. (2022). Cancer statistics in China and United States, 2022: profiles, trends, and determinants. Chinese medical journal, 135(05), 584-590.

Yehya, A. H., Asif, M., Majid, A. M. A., & Oon, C. E. (2023). Polymolecular botanical drug of Orthosiphon stamineus extract (C5OSEW5050ESA) as a complementary therapy to overcome gemcitabine resistance in pancreatic cancer cells. Journal of Traditional and Complementary Medicine, 13(1), 39-50.

Zhong, H., & Bowen, J. P. (2006). Antiangiogenesis drug design: multiple pathways targeting tumor vasculature. Current medicinal chemistry, 13(8), 849-862.