Activation of the Parthanatos Signaling Pathway by the Synergistic Combination of Cisplatin and Resveratrol in Tongue Cancer Cells

Year 2026, Volume: 12 Issue: 1, 27 - 40, 27.02.2026

Negar Taghavi Pourianazar

https://izlik.org/JA43WK23WZ

Abstract

Tongue cancer is an aggressive oral malignancy with limited treatment success due to high invasion rates and chemotherapeutic resistance. Despite conventional therapies like surgery and radiotherapy, resistance to cornerstone drugs such as cisplatin remains a major obstacle, negatively impacting patient survival. Combining anti-cancer agents with distinct mechanisms is a critical strategy to overcome resistance and prevent tumor recurrence. Cisplatin induces DNA damage and apoptosis but is limited by systemic toxicity and acquired resistance. Resveratrol, a natural polyphenol with potent anticancer and antioxidant properties, has shown efficacy against various cancers, including multidrug-resistant cells. This study comprehensively investigated the synergistic cytotoxic effects of the cisplatin and resveratrol combination on the OSC-19 human tongue cancer cell line and its molecular relationship with the parthanatos cell death pathway.
Cell viability was evaluated using the MTT assay, revealing that the combination therapy significantly inhibited proliferation compared to single-agent treatments, generating a potent synergistic response. To elucidate the molecular mechanism, mRNA expression levels of PARP-1 and AIF, key components of the parthanatos pathway, were analyzed via real-time PCR (RT-PCR). Findings demonstrated that the combination markedly triggered PARP-1 activation and upregulated AIF expression, thereby activating the parthanatos pathway. Distinct from classical apoptosis, parthanatos is a caspase-independent cell death form characterized by PARP-1 hyperactivation and the translocation of AIF from the mitochondria to the nucleus. This study provides scientific evidence that the cisplatin and resveratrol combination represents a novel and effective therapeutic approach to overcoming chemotherapy resistance in tongue cancer cells by inducing parthanatos.

Keywords

Human Tongue Cancer , Cisplatin , Resveratrol , Synergistic Effect , PARP-1

İnsan Dil Kanseri Hücrelerinde Sisplatin ve Resveratrol Sinerjistik Kombinasyonu ile Parthanatos Sinyal Yolağının Aktivasyonu

https://izlik.org/JA43WK23WZ

Abstract

Dil kanseri, dünya genelinde yaygın ve tedavi başarısı sınırlı bir oral kanser türüdür. Cerrahi, radyoterapi ve kemoterapi gibi mevcut tedavilere rağmen, yüksek invazyon ve metastaz oranları ile kemoterapötik ilaçlara karşı gelişen direnç, hastaların yaşam kalitesini ve sağkalımını olumsuz etkilemektedir. Özellikle sisplatin gibi temel kemoterapötik ajanlara karşı gelişen direnç, tedavi önündeki en büyük engellerden biridir. Bu direncin üstesinden gelmek için farklı etki mekanizmalarına sahip anti-kanser ajanlarının kombinasyon halinde kullanılması kritik bir stratejidir; zira tek ilaç tedavileri sıklıkla dirençli mutasyonlara ve tümör nüksetmesine yol açabilmektedir. Sisplatin, DNA hasarı ve apoptoz indüksiyonu yoluyla etki gösteren güçlü bir kemoterapötiktir, ancak yan etkileri ve direnç gelişimi kullanımını kısıtlar. Resveratrol ise üzüm gibi bitkilerde bulunan, antikanser ve antioksidan özelliklere sahip doğal bir mikrobesindir. Çeşitli kanser türlerinde anti-proliferatif ve pro-apoptotik aktivite gösterdiği, ayrıca çoklu ilaç direncine sahip tümör hücrelerine karşı da etkili olduğu kanıtlanmıştır. Bu çalışmada, sisplatin ve resveratrol kombinasyonunun OSC-19 insan dil kanseri hücre hattı üzerindeki sinerjistik sitotoksik etkileri ve bu etkilerin moleküler düzeyde parthanatos hücre ölümü yolağı ile olan ilişkisi kapsamlı bir şekilde araştırılmıştır.
Hücre canlılığı üzerindeki etkiler MTT testi ile değerlendirilmiş; elde edilen veriler kombinasyon tedavisinin, tekli ilaç uygulamalarına kıyasla hücre proliferasyonunu anlamlı düzeyde inhibe ettiğini ve güçlü bir sinerjistik sitotoksik yanıt oluşturduğunu ortaya koymuştur. Moleküler mekanizmayı aydınlatmak amacıyla, parthanatos yolağının kilit bileşenleri olan PARP-1 ve AIF genlerinin mRNA ekspresyon düzeyleri gerçek zamanlı polimeraz zincir reaksiyonu (RT-PCR) yöntemi ile analiz edilmiştir. Bulgular, kombinasyon tedavisinin PARP-1 aktivasyonunu belirgin şekilde tetiklediğini ve buna bağlı olarak AIF ekspresyonunu yukarı regüle ederek parthanatos yolağını aktive ettiğini göstermiştir. Parthanatos, klasik apoptozdan farklı olarak PARP-1 hiperaktivasyonu ve AIF'in mitokondriden çekirdeğe translokasyonu ile karakterize edilen, kaspaz bağımsız bir hücre ölümü formudur. Bu çalışma, sisplatin ve resveratrol kombinasyonunun dil kanseri hücrelerinde parthanatosu indükleyerek kemoterapi direncini kırmada ve tedavi etkinliğini artırmada yeni ve etkili bir terapötik yaklaşım olabileceğini bilimsel verilerle ortaya koymaktadır.

Keywords

İnsan Dil Kanseri , Sisplatin , Resveratrol , Sinerjistik Etki , PARP-1

References

• Baguley, B. C. (2002). Novel strategies for overcoming multidrug resistance in cancer. BioDrugs, 16(2), 97–103.
• Balachander, K., Vijayashree Priyadharsini, J., & Paramasivam, A. (2022). Advances in oral cancer early diagnosis and treatment strategies with liquid biopsy-based approaches. Oral Oncology, 134, 106108.
• Bayat Mokhtari, R., Homayouni, T. S., Baluch, N., Morgatskaya, E., Kumar, S., Das, B., & Yeger, H. (2017). Combination therapy in combating cancer. Oncotarget, 8(23), 38022–38043.
• Bray, F., Laversanne, M., Sung, H., Ferlay, J., Siegel, R. L., Soerjomataram, I., & Jemal, A. (2024). Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer Journal for Clinicians, 74(3), 229–263.
• Chou, T. C. (2010). Drug combination studies and their synergy quantification using the Chou–Talalay method. Cancer Research, 70(2), 440–446.
• Dasari, S., & Tchounwou, P. B. (2014). Cisplatin in cancer therapy: Molecular mechanisms of action. European Journal of Pharmacology, 740, 364–378.
• Elshaer, M., Chen, Y., Wang, X. J., & Tang, X. (2018). Resveratrol: An overview of its anti-cancer mechanisms. Life Sciences, 207, 340–349.
• Fatokun, A. A., Dawson, V. L., & Dawson, T. M. (2014). Parthanatos: Mitochondrial-linked mechanisms and therapeutic opportunities. British Journal of Pharmacology, 171(8), 2000–2016.
• Georges, P., Rajagopalan, K., Leon, C., Singh, P., Ahmad, N., Nader, K., & Kubicek, G. J. (2014). Chemotherapy advances in locally advanced head and neck cancer. World Journal of Clinical Oncology, 5(5), 966–972.
• He, W., McCoy, M. D., Riggins, R. B., Beckman, R. A., & Yeang, C. H. (2025). Personalized cancer treatment strategies incorporating irreversible and reversible drug resistance mechanisms. NPJ Systems Biology and Applications, 11(1), 70.
• Hervieu, M., Legrand, A. J., Floquet, E., Idziorek, T., Spriet, C., Monté, D., Villeret, V., Aumercier, M., & Choul-Li, S. (2025). PARP-1 inhibition increases oxidative stress in Ets-1-expressing MDA-MB-231 breast cancer cells. Cancer Reports, 8(1), e70119.
• Holoye, P. Y., Byers, R. M., Gard, D. A., Goepfert, H., Guillamondegui, O. M., & Jesse, R. H. (1978). Combination chemotherapy of head and neck cancer. Cancer, 42(4), 1661–1669.
• Huang, F., Wu, X. N., Chen, J., Wang, W. X., & Lu, Z. F. (2014). Resveratrol reverses multidrug resistance in human breast cancer doxorubicin-resistant cells. Experimental and Therapeutic Medicine, 7(6), 1611–1616.
• Keke Li, Li, J., Li, Z., Men, L., Zuo, H., & Gong, X. (2024). Cisplatin-based combination therapies: Their efficacy with a focus on ginsenosides coadministration. Pharmacological Research, 203, 107175.
• Kotsopoulos, I. C., Kucukmetin, A., Mukhopadhyay, A., Lunec, J., & Curtin, N. J. (2016). Poly(ADP-ribose) polymerase in cervical cancer pathogenesis: Mechanism and potential role for PARP inhibitors. International Journal of Gynecological Cancer, 26(4), 763–769.
• Koushki, M., Amiri-Dashatan, N., Ahmadi, N., Abbaszadeh, H. A., & Rezaei- Tavirani, M. (2018). Resveratrol: A miraculous natural compound for diseases treatment. Food Science & Nutrition, 6(8), 2473–2490. Kursvietiene, L., Kopustinskiene, D. M., Staneviciene, I., Mongirdiene, A.,
• Kubová, K., Masteikova, R., & Bernatoniene, J. (2023). Anti-cancer properties of resveratrol: A focus on its impact on mitochondrial functions. Antioxidants, 12(12), 2056.
• Li, W., Li, C., Ma, L., & Jin, F. (2020). Resveratrol inhibits viability and induces apoptosis in the small-cell lung cancer H446 cell line via the PI3K/Akt/c- Myc pathway. Oncology Reports, 44(5), 1821–1830.
• Lu, L., Zhan, M., Li, X. Y., Zhang, H., Dauphars, D. J., Jiang, J., Yin, H., Li, S. Y., Luo, S., Li, Y., & He, Y. W. (2022). Clinically approved combination immunotherapy: Current status, limitations, and future perspective. Current Research in Immunology, 3, 118–127.
• Makovec, T. (2019). Cisplatin and beyond: Molecular mechanisms of action and drug resistance development in cancer chemotherapy. Radiology and Oncology, 53(2), 148–158.
• Mazloum-Ardakani, M., Barazesh, B., Moshtaghioun, S. M., & Sheikhha, M. H. (2019). Designing and optimization of an electrochemical substitute for the MTT cell viability assay. Scientific Reports, 9(1), 14966.
• Minerva, Bhat, A., Verma, S., Chander, G., Jamwal, R. S., Sharma, B., Katyal, T., Kumar, R., & Shah, R. (2023). Cisplatin-based combination therapy for cancer. Journal of Cancer Research and Therapeutics, 19(3), 530–536.
• Mosier, K. M., Graner, B. D., & Gray, B. R. (2025). Trends in head and neck cancer: Oral cavity carcinoma and what the radiologist needs to know. Radiology: Imaging Cancer, 7(6), e250154.
• Soni, H., Kaminski, D., Gangaraju, R., & Adebiyi, A. (2018). Cisplatin-induced oxidative stress stimulates renal Fas ligand shedding. Renal Failure, 40(1), 314–322.
• Tanida, S., Mizoshita, T., Ozeki, K., Tsukamoto, H., Kamiya, T., Kataoka, H., Sakamuro, D., & Joh, T. (2012). Mechanisms of cisplatin-induced apoptosis and of cisplatin sensitivity: Potential of BIN1 to act as a potent predictor of cisplatin sensitivity in gastric cancer treatment. International Journal of Surgical Oncology, 2012, 862879.
• Villaret, A. B., Cappiello, J., Piazza, C., Pedruzzi, B., & Nicolai, P. (2008). Quality of life in patients treated for cancer of the oral cavity requiring reconstruction: A prospective study. Acta Otorhinolaryngologica Italica, 28(3), 120–125.
• Wu, Z., Liu, B., E, C., Liu, J., Zhang, Q., Liu, J., Chen, N., Chen, R., & Zhu, R. (2015). Resveratrol inhibits the proliferation of human melanoma cells by inducing G1/S cell cycle arrest and apoptosis. Molecular Medicine Reports, 11(1), 400–404.