Potential New Therapeutic Approaches for Cisplatin-Resistant Testicular Germ Cell Tumors

Background: Testicular germ cell tumors (TGCTs), a group of heterogeneous neoplasms, are the most frequent tumors of teenagers and young men, with the incidence rising worldwide. High cure rates can be achieved through cisplatin (CDDP)-based treatment, but approximately 10% of patients present refractory disease and virtually no treatment alternatives. Here, we explored new strategies to treat CDDP-resistant.

Methods: In vitro TGCT CDDP-resistance model was established and differential mRNA expression profiles were evaluated using NanoString technology. Then, TGCT cell lines were treated with four potential drugs (PCNA-I1, ML323, T2AA, and MG-132) to overcome CDDP-resistance.

Results: We found several differentially expressed genes related to DNA repair and cell cycle regulation on CDDP-resistant cell line (NTERA-2R) compared to parental cell line (NTERA-2P), and the proteasome inhibitor MG-132 demonstrated cytotoxic activity in all cell lines evaluated, even at a nanomolar range. MG-132 also enhanced cell lines' sensitivity to CDDP, increasing apoptosis in both NTERA-2P and NTERA-2R.

Conclusions: MG-132 emerges as a potential new drug to treat CDDP-resistant TGCT. Targeted therapy based on molecular mechanism insights may contribute to overcome acquired chemotherapy CDDP-resistance.

 

Comments:

Summary: The study aimed to explore new strategies to treat cisplatin (CDDP)-resistant testicular germ cell tumors (TGCTs), which are the most frequent tumors in teenagers and young men. The researchers established an in vitro CDDP-resistance model using TGCT cell lines and analyzed the differential mRNA expression profiles using NanoString technology. They then treated the cell lines with four potential drugs (PCNA-I1, ML323, T2AA, and MG-132) to overcome CDDP-resistance.

The results showed that several genes related to DNA repair and cell cycle regulation were differentially expressed in the CDDP-resistant cell line (NTERA-2R) compared to the parental cell line (NTERA-2P). Among the tested drugs, the proteasome inhibitor MG-132 demonstrated cytotoxic activity across all evaluated cell lines, even at low concentrations. Furthermore, MG-132 enhanced the sensitivity of the cell lines to CDDP and increased apoptosis in both the parental and resistant cell lines (NTERA-2P and NTERA-2R).

Based on these findings, MG-132 emerges as a potential new drug for the treatment of CDDP-resistant TGCTs. The study highlights the importance of targeted therapy based on molecular mechanisms to overcome acquired chemotherapy resistance, providing insights for future research in this field.

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S4476	PCNA-I1	PCNA-I1 is a selective inhibitor of proliferating cell nuclear antigen (PCNA, a potential anticancer target). PCNA-I1 selectively binds to PCNA trimers with Kd of ~0.2 to 0.4 μM. PCNA-I1 inhibits the growth of tumor cells of various tissue types with IC50 of ~0.2 μM. PCNA-I1 induces DNA damage and apoptosis in both LNCaP and PC-3 cells. PCNA-I1 also induces autophagy in PC-3 cells.

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Autophagy DNA/RNA Synthesis Apoptosis related