Polysaccharides from Lentinus edodes prevent acquired drug resistance to docetaxel in prostate cancer cells by decreasing the TGF-ß1 secretion of cancer-associated fibroblasts.

Prostate cancer is one of the most prevalent lethal diseases among men globally. In the treatment of prostate cancer, the limited therapeutic efficacy of the standard non-hormonal systemic therapy docetaxel (DTX) represents an important challenge. Cancer-associated fibroblasts (CAFs) play a crucial role in resistance to therapy because of their prevalence and functional pleiotropy in tumor environments. Our previous research revealed that MPSSS, a novel polysaccharide extracted from Lentinus edodes, could significantly attenuate the immunosuppressive function of myeloid suppressor cells and CAFs. In this study, we investigated whether MPSSS could potentiate the efficacy of DTX against prostate cancer by inhibiting CAF-induced chemoresistance and elucidated its underlying mechanisms. The sensitivity of PC-3 prostate cancer cells cultured with conditioned medium derived from CAFs (CAF-CM) to DTX was assessed. The resistance effect induced by CAF-CM was abolished when CAFs were pretreated with MPSSS. Bioinformatic analysis of datasets from the Gene Expression Omnibus database revealed the activation of the transforming growth factor ß1 (TGF-ß1) signaling pathway in DTX-resistant cells. Based on this finding, we demonstrated that treatment with the TGF-ß1 receptor inhibitor SB525334 reversed DTX resistance in CAFs, suggesting that TGF-ß1 secreted by CAFs was a crucial intermediary in the development of DTX resistance in PC3 cells. Further research revealed that MPSSS decreases the secretion of TGF-ß1 by inhibiting the JAK2/STAT3 pathway via Toll-like receptor 4 in CAFs. Overall, MPSSS might be a potential adjuvant treatment for DTX resistance in prostate cancer.

A novel targeted multifunctional nanoplatform for visual chemo-hyperthermia synergy therapy on metastatic lymph nodes via lymphatic delivery.

BACKGROUND: Distant metastasis to vital organs is the major contributor to breast cancer mortality, and regional lymph node metastasis is an important facilitator of distant metastasis and recurrence in this cancer. The early diagnosis and precise treatment of lymph node metastasis are crucial for staging and prognosis in breast cancer. Herein, we report a visualized precision medicine nanoplatform of metastatic lymph nodes for ultrasonic/photoacoustic (US/PA) dual modal imaging-guided in situ targeted hyperthermia-combined chemotherapy. RESULTS: Carbon nanoparticles (CNs), approved by the China Food and Drug Administration, were loaded with docetaxel and rationally combined with anti-hypoxia-inducible factor 1α antibody-modified poly (lactic-co-glycolic acid) (PLGA) nanoparticles to achieve the combination of passive targeting at the lymph nodes and intracellular targeting at HIF 1α factor. The accumulation and retention of nanoparticles in metastatic lymph nodes via lymphatic delivery were enhanced. Docetaxel could be effectively offloaded by CNs that have active carbon nanoparticles, and the PLGA membrane prevented drug leakage. The nanoparticles exhibited excellent photothermal performance with a photothermal conversion efficiency of 28.9%, killing tumor cells in metastatic lymph nodes through hyperthermia. In vitro and in vivo systematic evaluations revealed that hyperpyrexia triggered the rupture of nanoparticles caused by the phase transition of perfluorohexane, resulting in docetaxel release for achieving in situ hyperthermia-combined chemotherapy. CONCLUSIONS: The laser-triggered highly efficient in situ chemotherapy nanosystem achieves targeted synergistic chemo-hyperthermia treatment of metastatic lymph nodes, and lymphatic delivery represents a strategy to avoid additional injury caused by drugs entering the blood circulation.