Considering the limitations of monotherapies due to chemoresistance and side effects, this research aimed to determine whether low doses of sulforaphane (SFN) combined with docetaxel (DCT) could enhance therapeutic efficacy. Prostate cancer cell lines LNCaP and PC-3 were treated with individual IC50 doses of SFN and DCT and half-reduced IC50 values for the SFN:DCT combination. Metabolic markers, including glucose consumption, lactate production, reactive oxygen species (ROS), mitochondrial mass, and caspase activity, were assessed. In LNCaP cells, the SFN:DCT combination reduced cell viability to 50%, comparable to DCT monotherapy (48%). Caspase 3 activation was also higher with SFN:DCT (2.4 ± 0.75 RFU) than DCT alone (2.1 ± 0.47 RFU), while caspase 8 activation remained comparable, indicating equivalent effectiveness at lower concentrations. In PC-3 cells, the combination induced caspase 3 activation (1.16 ± 0.0484 RFU) at levels slightly lower than DCT (1.51 ± 0.2062 RFU) but achieved greater reductions in mitochondrial mass, reflecting its ability to target metabolic vulnerabilities in aggressive phenotypes. Our findings suggest that the SFN:DCT combination is a promising strategy for early-stage prostate cancer. By achieving comparable efficacy to DCT monotherapy at low doses, the SFN:DCT combination maintains the therapeutic impact, mitigating the adverse effects of conventional DCT treatment.

Chimeric antigen receptor (CAR) therapies are emerging as promising strategies, particularly for metastatic castration-resistant prostate cancer (PCa), as they can act independently of the androgen receptor axis. Adapter CAR-T cell platforms, such as the RevCAR system, offer precise therapeutic control and tumor targeting via small, rapidly eliminated tumor-specific adapters. To enable more convenient late-stage RevCAR-T therapy in PCa patients, allowing for discontinuous reverse target module (RevTM) infusion, we developed novel, larger IgG4-based RevTMs targeting prostate stem cell antigen (PSCA) and benchmarked them against previously described smaller adapter formats. Within the RevCAR system, PSCA-IgG4 RevTMs effectively mediated PCa killing at low effector-to-target ratios and low RevTM concentrations in a strictly antigen-dependent manner. Oncolytic activity was accompanied by a rapid and pronounced release of proinflammatory cytokines across a broad RevTM concentration range, which is particularly advantageous for immunologically cold PCa. Finally, anti-tumor activity was confirmed in a short-term mouse model. Preliminary PET studies further indicate slow blood elimination and tumor-specific accumulation of novel IgG4-RevTMs. Together, these data position PSCA-IgG4 RevTMs as promising candidates for stepwise RevCAR-T treatment in PCa, in which short-lived scFv-RevTMs are initially used to ensure a rapid safety switch, followed by larger IgG4-RevTMs once the risk profile is known.

Dimethyl fumarate (DMF) is a clinically approved fumarate ester with pleiotropic effects and a promising candidate for drug repurposing in cancer. Here, we investigated whether low-dose DMF could modulate docetaxel (DCT) responses in prostate cancer cells. PC-3, LNCaP, and RWPE-1 cells were exposed to DMF and DCT individually or in combination, and cell viability, drug interaction profiles, apoptosis, oxidative stress, mitochondrial mass, glutathione status, glucose consumption, lactate production, LDHA/SOD2 expression, and oxygen consumption were evaluated. Low-dose DMF and DCT were well-tolerated in RWPE-1 normal prostate cells. In prostate cancer cells, the DMF–DCT combination was cytotoxic and strongly dose- and ratio-dependent, with the most favorable responses at higher exposures and under balanced or DCT-enriched regimens. DMF-DCT-treated LNCaP cells showed reduced viability, decreased lactate production, increased glucose consumption, mitochondrial dysfunction, oxidative stress, downregulation of LDHA and SOD2, and caspase-associated apoptosis. In contrast, PC-3 cells showed greater combinatorial susceptibility, a docetaxel dose-sparing effect, and a low glycolytic profile, with concomitant cytotoxicity and mitochondrial dysfunction. These findings identify DMF as a context-dependent metabolic modulator of docetaxel response, supporting further evaluation of DMF–DCT combinations as a potential therapeutic strategy in prostate cancer.

The Prostate Stem Cell Antigen (PSCA) is not only overexpressed in prostate cancer (PC) but also in many other tumors, including cervical cancer (CC). The adaptor chimeric antigen receptor (CAR) platform RevCAR can be used for immunotargeting of PSCA-expressing tumor cells. We found that the CC cell line SiHa natively expresses PSCA. The expression was sufficient for redirection of RevCAR T-cells using recently described RevCAR target modules (RevTMs) directed against PSCA. Like almost all PC cell lines, however, SiHa cells also downregulate their PSCA expression in cell culture. To overcome this limitation, we established artificially PSCA-overexpressing SiHa cells. Retargeting of RevCAR T-cells strictly depends on PSCA-directed RevTMs and PSCA-expressing target cells. It leads to (i) upregulation of CD69, Perforin and Granzyme B, (ii) lysis of target cells with EC₅₀ values in the picomolar range, and (iii) cytokine secretion of IFN-γ, TNF-α, GM-CSF and IL-2. Phenotypic analysis shows a prominent increase in memory RevCAR T-cells but only a slight increase in exhausted cells, indicating a low level of tonic signaling of RevCAR T-cells. Together, our data supports an efficient and safe immunotargeting of PSCA-expressing CC cells with the RevCAR technology.

La enfermedad por coronavirus 2019 (COVID-19) ha generado un impacto a gran escala en la salud pública mundial debido a su rápida propagación y a su alta capacidad de contagio, adaptación y evolución. En esta revisión se describen las diferencias entre mutaciones, variantes, linajes y cepas de Coronavirus del Síndrome Respiratorio Agudo Severo 2 (SARS-CoV-2); se listan las principales mutaciones presentes en las variantes de interés (VOI por sus siglas en inglés) y variantes de preocupación (VOC por sus siglas en inglés) de SARS-CoV-2 y su distribución geográfica; y finalmente, se analiza la implicación que tienen las nuevas variantes sobre la efectividad de las vacunas, evidenciando la importancia de la vigilancia genómica de SARS-CoV-2 en la era post vacunación.