New NO- and H2S-releasing doxorubicins as targeted therapy against chemoresistance in castration-resistant prostate cancer: in vitro and in vivo evaluations.
Elisabetta BigagliCristina LuceriMaria De AngiolettiKonstantin ChegaevMario D'AmbrosioChiara RigantiElena GazzanoSimona SaponaraMariangela LonginiFrancesca LuceriLorenzo CinciPublished in: Investigational new drugs (2018)
Chemotherapy for castration-resistant prostate cancer (CRPC) is only temporarily effective due to the onset of chemoresistance. We investigated the efficacy of NO- and H2S-releasing doxorubicins (NitDox and H2SDox) in overcoming drug resistance and evaluated their safety. New and innovative NO- and H2S-releasing doxorubicins (NitDox and H2SDox) showed a good intracellular accumulation and high cytotoxic activity in vitro in an androgen-independent and doxorubicin-resistant DU-145 prostate cancer cell line. Nude mice were subcutaneously injected with 4*106 DU-145 cells and treated once a week for 3 weeks with 5 mg/kg doxorubicin, NitDox, H2SDox or vehicle, i.p. Animal weight, tumor volume, intra-tumoral drug accumulation, apoptosis and the presence of nitrotyrosine and sulfhydryl (SH) groups within the tumor, were evaluated. Cardiotoxicity was assessed by measuring troponin plasma levels and the left ventricular wall thickness. In vivo, NitDox and H2SDox accumulated inside the tumors, significantly reduced tumor volumes by 60%, increased the percentage of apoptotic cells in both the inner and the outer parts of the tumors and the presence of nitrotyrosine and SH groups. Doxorubicin treatment was associated with reduced body weight and cardiotoxicity. On the contrary, NitDox and H2SDox were well tolerated and had a better safety profile. Combining efficacy with reduced cardiovascular side effects, NitDox and H2SDox are promising novel therapeutic agents for reversing chemoresistance in CRCP.
Keyphrases
- cell cycle arrest
- body weight
- induced apoptosis
- cell death
- prostate cancer
- left ventricular
- drug delivery
- endoplasmic reticulum stress
- oxidative stress
- cancer therapy
- pi k akt
- heart failure
- body mass index
- type diabetes
- acute myocardial infarction
- radical prostatectomy
- metabolic syndrome
- optical coherence tomography
- atomic force microscopy
- adipose tissue
- acute coronary syndrome
- anti inflammatory
- high fat diet induced
- skeletal muscle
- electronic health record
- newly diagnosed
- wild type