Antioksidan Kullanımının Meme Kanseri Tedavisi Üzerindeki Etkilerinin Araştırılması
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Drug resistance against chemotherapy is one of the main factors limitating the success of cancer treatment. Several studies have reported that the expression level of the glutathione S-transferase P1 (GSTP1) isozyme from glutathione S-transferases is increased in many cancer cell lines. GSTP1 induces drug resistance by inactivating chemotherapeutic agents with glutathione (GSH) conjugation and also acts as an endogenous inhibitor of JNK1 (c-Jun N-terminal kinase1), a member of the mitogen-activated protein kinase (MAPK) cascade involved in apoptosis. The chlorophyllin, an antioxidant molecule, has been shown to have an inhibitory effect on GSTP1 by our group. The antioxidant N-acetyl cysteine (NAC) is the precursor molecule of GSH, the cosubstrate of GSTP1. This study aimed to investigate the effects of chlorophyllin and NAC on breast cancer treatment. For this purpose, the effects of chlorophyllin, NAC and an anti-cancer drug (docetaxel), were investigated in a breast cancer model created by using a treatment-resistant triple (ER, PR, HER2) negative 4T1 breast cancer cells in vivo / in vitro and transcriptomically (in silico). In this study, GST activity, GSH levels, JNK signaling pathway component c-Jun, and the apoptotic protein p38 and caspase 8-9 levels were also investigated in 4T1 cell lysates and tumor tissues. Transcriptomic analyzes were performed on RNA sequencing data obtained from tumor tissues to investigate the tendency of cancer cells to apoptosis and / or proliferation in detail. As a result, chlorophyllin significantly increased the effectiveness of docetaxel used in cancer treatment both in vivo and in vitro (p<0.05). According to the transcriptomic study results, the combination of GSTP1 inhibitor chlorophyllin and docetaxel activated many cancer-related suppressed mechanisms MAPK, Wnt, oxytocin signaling pathways and autophagy. On the other hand, the anti-apoptotic phospholipase D (FLD) signaling pathway was also activated, despite the activation of apoptotic signaling pathways by suppressing drug resistance. Therefore, FLD signaling pathway could be a new therapeutic target in addition to drug resistance in cancer treatment. In this study, it was concluded that despite the anti-drug resistance and apoptosis-inducing effects of chlorophyllin, a GSTP1 inhibitor with antioxidant properties, in the treatment of breast cancer, antioxidant molecules such as NAC may negatively affect the prognosis of cancer treatment by suppressing apoptotic signaling pathways.