Investigation of Possible Synergistic Effects of Co-administration of Acetylsalicylic Acid and Salicylic Acid with Paclitaxel on Autophagy, ER stress and Apoptotic Cell Death in Prostate Cancer Cells

Öz

Prostate cancer is the second most common type of cancer in men and the fifth leading cause of cancer-related death worldwide. Although chemotherapeutics and anti-androgens are frequently used approaches in the treatment of prostate cancer, their use is limited due to acquired drug resistance and developing castration resistance mechanisms. For this reason, the need for new approaches continues to eliminate the side effects of existing treatments and to improve the therapeutic efficacy of currently used agents. In the present study, we investigated the effect of acetylsalicylic acid (ASA) and salicylic acid (SA) alone or their combination with Paclitaxel which is an anti-mitotic agent frequently used in the treatment of various chemotherapy-resistant cancer types, on the PERK branch of unfolded protein response (UPR) signaling, autophagy and apoptotic cell death in prostate cancer cells. Our findings showed that the combination of Paclitaxel with ASA and SA has strong anti-cancer effects on prostate cancer cells by inducing autophagy, causing CHOP stimulation via the PERK arm of the UPR and activating apoptotic proteins caspase-3 and PARP-1. These results suggest that the combination of ASA and SA with Paclitaxel may offer an effective treatment approach by improving the anti-cancer efficacy of Paclitaxel in the treatment of prostate cancer.

Anahtar Kelimeler

• Apoptosis
• Acetylsalicylic acid
• Unfolded Protein Response
• Salicylic acid
• Paclitaxel
• Prostate cancer
• Autophagy

Asetilsalisilik Asit ve Salisilik Asitin Paklitaksel ile Eş Uygulamasının Prostat Kanseri Hücreleri Üzerindeki Olası Sinerjistik Etkilerinin Otofaji, ER stresi ve Apoptotik Hücre Ölümü ile İlişkisinin Araştırılması

Öz

Prostat kanseri, dünya genelinde erkeklerde en sık görülen ikinci kanser türüdür ve kansere bağlı ölüm nedenleri arasında beşinci sırada yer almaktadır. Kemoterapötikler ve anti-androjenler prostat kanseri tedavisinde sıklıkla kullanılan yaklaşımlar olmasına karşın kazanılan ilaç direnci ve gelişen kastrasyona direnç mekanizmaları nedeniyle kullanımları sınırlanmaktadır. Bu nedenle mevcut tedavilere ait yan etkilerin giderilmesi ve hali hazırda kullanılan ajanların terapötik etkinliklerinin geliştirilebilmesi için yeni yaklaşımlara olan ihtiyaç devam etmektedir. Bu çalışma kapsamında, asetilsalisilik asit (ASA) ve salisilik asit (SA)’in tek başına veya kemoterapiye dirençli çeşitli kanser türlerinin tedavisinde sıklıkla kullanılan bir anti-mitotik ajan olan Paklitaksel ile kombine uygulamalarının prostat kanseri hücrelerinde katlanmamış protein yanıtı (UPR) sinyalinin PERK kolu, otofaji ve apoptotik hücre ölümü aracılı olası etki mekanizmaları incelendi. Bulgularımız, Paklitaksel’in ASA ve SA ile kombinasyonunun otofaji mekanizmasını uyardığını ve UPR’nin PERK kolu aktivasyonu aracılı CHOP uyarımına ve apoptotik proteinler olan kaspaz-3 ve PARP-1 kesimine neden olarak prostat kanseri hücrelerinde güçlü anti-kanser etkiler sergilediğini göstermiştir. Bu sonuçlar, prostat kanseri tedavisinde ASA ve SA’nın Paklitaksel ile kombinasyonunun Paklitaksel’in anti-kanser etkinliğini geliştirerek etkili bir tedavi yaklaşımı sunabileceğini düşündürmektedir.

Anahtar Kelimeler

• : Apoptozis
• Asetilsalisilik asit
• Katlanmamış protein yanıtı
• Salisilik asit
• Paklitaksel
• Prostat kanseri
• Otofaji

Kaynakça

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