Prostat Kanseri Hücrelerinde Kafein Sisplatinin Anti-tümorijenik Etkisini Güçlendirir

Abstract

Giriş ve Amaç: Günümüzde prostat kanseri (PCa) tedavisinde cerrahi, androjen ablasyon tedavisi ve kemoterapi gibi çok sayıda yaklaşım bulunmaktadır. Ancak, androjen reseptörü (AR) hedefli terapiler veya mevcut terapilerin doğal bileşiklerle kombinasyonunun geliştirilmesine halen ihtiyaç duyulmaktadır. Sisplatin çeşitli solid tümörlerin tedavisinde yaygın olarak kullanılan ilk platin bazlı kemoterapötik ajanlardan birisidir. Kafein (Cfn) altmıştan fazla bitki türünde doğal olarak bulunan ve dünya çapında en sık tüketilen nöroaktif doğal ürün olan ksantin türevi bir alkaloittir. Anti-oksidan, anti-inflamatuar ve anti-kanser gibi çeşitli biyokimyasal etkilere sahiptir. Bu çalışmada, yaygın olarak kullanılan bir kemoterapötik ajan olan sisplatinin kafein ile kombinasyonunun PCa hücreleri üzerindeki etkilerini araştırdık. Gereç ve Yöntemler: Total-p38 MAPK, fosforile-(Thr180/Tyr182) p38 MAPK, total NF-κB, fosforile-(Ser536) NF-κB, Siklin A2, Siklin B1, Siklin E1, AR, PSA ve VEGF-A protein ifadesi düzeyleri immünoblotlama çalışmaları ile insan prostat kanseri hücre hattı olan LNCaP hücrelerinde incelenmiştir. Sonuçlar: Elde ettiğimiz sonuçlar, Cfn'nin siklin A2, B1 ve E1 düzeylerini azaltarak, androjenik sinyal ile ilişkili AR ve PSA düzeylerini ve anjiyojenik düzenleyici VEGF-A protein düzeylerini baskılayarak sisplatinin LNCaP hücreleri üzerindeki etkisini sinerjistik olarak doz-bağımlı bir şekilde arttırdığını gösterdi. Ayrıca, sisplatin kaynaklı p38 MAPK ve NF-κB aktivasyonunun Cfn uygulaması tarafından baskılandığını belirlendi. Tartışma: Sonuçlarımız, sisplatin ve Cfn'nin kombine kullanımının kemoterapötiklerin toksik dozunu azaltarak PCa tedavisinde etkili bir terapötik yaklaşım sunabileceğini göstermektedir.

Keywords

• Androjen reseptörü
• Kafein
• Sisplatin
• Prostat kanseri

Project Number

TSG-2021-8302, TAB-2020-8253

Caffeine Potentiate the Anti-tumorigenic Effect of Cisplatin in Prostate Cancer Cells

Abstract

Objective: Today, there are numerous approaches for prostate cancer (PCa) treatment, such as surgery, androgen ablation therapy and chemotherapy. However, there is still a need to develop new androgen receptor (AR)-targeted therapies or a combination of existing therapies with natural compounds. Cisplatin is the first platinum-based anti-cancer drug which is one of the widely used chemotherapeutic agents in the treatment of various solid tumors. Caffeine (Cfn) is a xanthine-derived alkaloid that occurs naturally in more than sixty plant species and is the most frequently consumed neuroactive natural product globally. It has various biochemical effects, including anti-oxidant, anti-inflammatory and anti-cancer. In the present study, we investigated the effects of the widely used chemotherapeutic agent cisplatin and its combination with caffeine on PCa cells. Materials and Methods: We examined the protein expression level of total-p38 mitogen-activated protein kinase (MAPK) phospho-(Thr180/Tyr182) p38 MAPK, total nuclear factor-κB (NF-κB), phospho-(Ser536) NF-κB, cyclin A2, cyclin B1, cyclin E1, androgen receptor (AR), prostate-specific antigen (PSA) and vascular endothelial growth factor A (VEGF-A) in human prostate cancer cell line LNCaP by immunoblotting assay. Results: Our results indicated that Cfn synergistically increased the effect of cisplatin on LNCaP cells in a dose-dependent manner by decreasing the cyclin A2, B1 and E1 levels, reducing androgenic signal-related AR and PSA levels and angiogenic regulator VEGF-A levels. Also, we found that cisplatin-induced p38 MAPK and NF-κB activation were suppressed by Cfn administration. Conclusion: Our results suggest that combinatory usage of cisplatin and the cost-effective agent Cfn may exhibit an effective therapeutic approach in the treatment of PCa by reducing the toxic dose of chemotherapeutics.

Keywords

• Androgen receptor
• Caffeine
• Cisplatin
• Prostate cancer

Supporting Institution

Süleyman Demirel Üniversitesi

Project Number

TSG-2021-8302, TAB-2020-8253

Thanks

We thank Suleyman Demirel University-Innovative Technologies Application and Research Center.

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