YENİ BİR SENOMORFİK İLAÇ ADAYI OLARAK HİDROKLOROTİYAZİD

Öz

Amaç: Konvansiyonel kanser tedavisinde kullanılan kemoterapötiklerin hem kanser hem de kanser olmayan hücrelerde hücresel senesensi indüklediği bilinmektedir. Senesent hücrelerin önemli özellikleri, hücre morfolojilerinde belirgin değişikliklerin olması ve bu hücrelerden senesens ilişkili sekretuvar fenotip (SASP) olarak adlandırılan çeşitli sitokin, kemokin, büyüme faktörü ve matriks metalloproteinazların salgılanmasıdır. SASP faktörlerinin parakrin etki ile tümör mikroçevresinde kemoterapötik ilaç direncine, kanser hücre proliferasyonuna ve migrasyonuna neden olduğu gösterilmiştir. Bu nedenle, seçici olarak senesent hücre sekresyonunu baskılayan senomorfik etkili ilaçların geliştirilmesi, kanser tedavisinde yeni bir adjuvan tedavi olarak önem kazanmıştır. Rho kinaz enzim inhibisyonunun senesent hücrelerin sekretuvar aktivitesini inhibe ettiği gösterilmiştir. Yakın zamanlı bir çalışmada ise hipertansiyon tedavisinde kullanılan diüretik ilaçlardan biri olan hidroklorotiyazidin Rho kinaz enzim inhibisyonu yaptığı gösterilmiştir. Bu çalışmamızda Rho kinaz inhibisyonu yaptığı gösterilen hidroklorotiyazidin yeni bir senomorfik ilaç olma potansiyelinin değerlendirilmesi amaçlanmıştır. Gereç ve Yöntem: Önceki çalışmalarımızda senesensi indüklediği belirlenen bir kemoterapötik olan doksorubisin ile HeLa hücrelerinde senesens indüklenmiştir. Daha sonra hidroklorotiyazid içeren ve içermeyen gruplarda senesent hücre sekretomu toplanarak bu sekretomlarda en belirgin SASP faktörlerinden biri olan IL-6’nın ölçülmesi ile senomorfik etkinlik değerlendirilmiştir. Sonuç ve Tartışma: Bu çalışmamızda elde ettiğimiz veriler hidroklorotiyazidin, doksorubisin ile indüklenen senesent HeLa kanser hücrelerinin hem hücre boyutunu hem de sekrete edilen IL-6 düzeyini azalttığını göstermektedir. Bu verilerimiz hidroklorotiyazidin senomorfik etkiye sahip olduğuna işaret etmektedir. Kemoterapötiklerin yanında onların istenmeyen etkilerini engelleyebilecek adjuvan tedavi olarak senomorfik ilaçların kullanılması, daha efektif bir kanser tedavisi sağlanması açısından önemlidir.

Anahtar Kelimeler

• Hidroklorotiyazid
• ilaç yeniden konumlandırma
• kanser
• senesens
• senomorfik ilaç

HYDROCHLOROTHIAZIDE AS A NEW SENOMORPHIC DRUG CANDIDATE

Öz

Objective: It is known that chemotherapeutics used in conventional cancer treatment induce cellular senescence in both cancer and non-cancerous cells. Important features of senescent cells include prominent changes in cell morphology and the secretion of various cytokines, chemokines, growth factors, and matrix metalloproteinases from these cells, called senescence-associated secretory phenotype (SASP). It has been shown that SASP factors cause chemotherapeutic drug resistance, cancer cell proliferation, and migration in the tumor microenvironment through a paracrine effect. Therefore, developing senomorphic drugs that selectively suppress senescent cell secretion has gained importance as a new adjuvant therapy in cancer treatment. Rho kinase enzyme inhibition has been shown to inhibit the secretory activity of senescent cells. A recent study showed that hydrochlorothiazide, one of the diuretic drugs used to treat hypertension, inhibits the Rho kinase enzyme. In this study, we aimed to evaluate the potential of hydrochlorothiazide, which has been shown to inhibit Rho kinase, as a new senomorphic drug. Material and Method: Senescence was induced in HeLa cells with doxorubicin, a chemotherapeutic that was determined to induce senescence in our previous studies. Then, senescent cell secretomes were collected in groups with and without hydrochlorothiazide, and senomorphic activity was evaluated by measuring IL-6, one of the most prominent SASP factors in these secretomes. Result and Discussion: The data obtained in this study show that hydrochlorothiazide reduces both cell size and secreted IL-6 levels in doxorubicin-induced senescent HeLa cancer cells. These data indicate that hydrochlorothiazide has a senomorphic effect. The use of senomorphic drugs as adjuvant therapy to prevent their undesirable effects is important for providing more effective cancer treatment.

Anahtar Kelimeler

• Cancer
• drug repositioning
• hydrochlorothiazide
• senescence
• senomorphic drug

Kaynakça

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