Cisplatin Cytotoxicity in Human Testicular Germ Cell Tumor Cell Lines Is Enhanced by the CDK4/6 Inhibitor Palbociclib

• Published in: Clinical genitourinary cancer Vol. 19; no. 4; pp. 316 - 324
• Main Authors: Rossini, Elisa, Bosatta, Valentina, Abate, Andrea, Fragni, Martina, Salvi, Valentina, Basnet, Ram Manohar, Zizioli, Daniela, Bosisio, Daniela, Piovani, Giovanna, Valcamonico, Francesca, Mirabella, Giuseppe, Berruti, Alfredo, Memo, Maurizio, Sigala, Sandra
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.08.2021
• Subjects: 833K cell line; Cell cycle; Combined treatment; In vivo animal model; NT2/D1 cell line; NT2/D1 cell line; NT2/D1; pRb; TGCT; 833K cell line; CI; HR; BEP; PTU; STR; Cell cycle; Combined treatment; FA; DMF; HER2; VIP; In vivo animal model; P-pRb
• ISSN: 1558-7673; 1938-0682
• DOI: 10.1016/j.clgc.2021.01.006

Cisplatin-based chemotherapy is the mainstay of pharmacological treatment of testicular germ cell tumors (TGCTs) that, together with early diagnosis, surgery, and/or radiotherapy, has dramatically improved the prognosis. However, under the pressure of such pharmacological therapy (both classical cytotoxic drugs and targeted therapy), cancer cells may develop resistance. Thus, combination therapy that may include cytotoxic drugs and targeted therapy could offer an advantage to curing cancers. Here, we investigated the in vitro and in vivo antitumor activity of cisplatin, as a single-agent or in combination with palbociclib. The cell viability of Ntera-2/cl.D1 (NT2/D1) and 833K after exposure to palbociclib and/or cisplatin was evaluated by MTT dye reduction assay and by ATPLite Luminescence Assay. Gene and protein expression was evaluated by quantitative reverse transcription polymerase chain reaction and by western blot. Flow cytometric cell-cycle analysis was performed, as well. The in vivo experiments were conducted on NT2/D1 xenografts in AB zebrafish embryos exposed to the drugs. Palbociclib and cisplatin decreased TGCT cell viability both in vitro and in vivo. This effect was additive when cells were exposed to the drug combination. In the NT2/D1 cell lines, the drug combination also exerted a positive effect with regard to delaying cell recovery after the toxic insult. In the combination experiments, cisplatin-induced cell accumulation in G2/M was predominant compared with the palbociclib effect. These results could provide the rationale for developing further studies to improve the pharmacological treatment of TGCTs, but they must be demonstrated in a dedicated clinical trial. Cisplatin-based chemotherapy is the choice for testicular germ cell tumor (TGCT) treatment. Here, we studied at a preclinical level whether the cisplatin combined with the Cdk4/6 inhibitor palbociclib could offer an advantage in TGCT cell models. Palbociclib and cisplatin decreased TGCT cell viability in vitro and in vivo. We suggest a rationale for designing a clinical study to evaluate this combination approach. [Display omitted]