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Apoptosis in Testis and Bladder Cancer Cells Following Cisplatin Treatment

Metastatic testicular germ cell tumors (TGCT) show an over 80% cure rate with cisplatin-based therapy, unlike most solid metastatic cancers resistant to chemotherapy. TGCTs are hypothesized to be sensitive due to reduced DNA repair capability and a higher tendency to undergo apoptosis, particularly involving non-mutated p53. Köberle et al. explored the role of apoptotic pathways in this sensitivity by examining cisplatin-induced activation in TGCT cells compared to resistant bladder cancer cells. Cisplatin-induced apoptosis was studied in three testis tumor cell (TTC) lines (8333, SuSa, GCT27) and three bladder cancer cell lines (MGH-U1, HT1376, RT112). After 1-hour exposure to cisplatin, the sub-G1 fraction indicating apoptosis was measured. TTC lines showed a stronger dose- and time-dependent apoptosis compared to bladder cancer cells. At 10 and 20 µM, testis tumor cells had significantly more apoptotic cells than bladder cancer cells (P = 0.0219) (Fig. 1A). From 48 hours post-treatment, apoptosis was significantly higher in testis cells with P-values of P = 0.0376 (48 h), P = 0.0063 (72 h), P = 0.0014 (96 h), and P = 0.0082 (120 h) (Fig. 1B). Greater PARP-1 cleavage further indicated higher apoptosis in TTC (Fig. 1C). These results align with previous findings of cisplatin hypersensitivity in TTC due to persistent DNA damage from reduced ICL repair (Fig. 1C).

Fig. 1. Determination of apoptosis in testis (filled symbols) and bladder (open symbols) cancer cells after treatment with cisplatin (Köberle B, Usanova S, et al., 2024).

Cell Killing Efficacy of Brentuximab Vedotin in Correlation with CD30 Expression

Testicular germ cell tumors (TGCTs), the most common cancer in young men, are generally treatable with chemotherapy. However, cisplatin-resistant TGCTs in young patients remain a challenge, prompting the need for new therapeutic approaches. Brentuximab vedotin, which targets CD30-a protein overexpressed in many TGCTs-offers a promising treatment option. Yeste-Velasco et al. evaluated the efficacy of brentuximab vedotin alone and with other chemotherapy drugs, considering its potential to target CD30, to enhance treatment outcomes for TGCTs. Dose-response curves for brentuximab vedotin were generated for all 12 TGCT cell lines (833K, 833KR, Susa, SusaR, GCT27, GCT27R, GCT44，TERA-1，NTERA-2，NCG2102, 577MF and TCam-2) using MTS assay (Fig. 2A and B). Sensitivity generally correlated with CD30 expression. Highly CD30-expressive 833K cells were the most sensitive (>500 times). However, NCG2012 cells, despite significant CD30 expression, didn’t respond until concentrations exceeded 5000 ng/ml, likely due to non-specific toxicity. TCam-2, with low CD30 expression, also showed no response until over 5000 ng/ml. CD30-negative lines 577MF and GCT44, and low-expressing TERA1, started responding above 1000 ng/ml. At 125,000 ng/ml, nearly all cells were killed in three days, but about 20% of GCT27 and TCAM2 survived.

Fig. 2. Brentuximab vedotin dose-response curves of TGCT cell lines (Yeste-Velasco M, Guo T, et al., 2019).