Upregulation of tumor suppressor PIAS3 by Honokiol promotes tumor cell apoptosis via selective inhibition of STAT3 tyrosine 705 phosphorylation.

The natural product Honokiol exhibits robust antitumor activity against a range of cancers, and it has also received approval to undergo phase I clinical trial testing. We confrmed that honokiol can promote the apoptotic death of tumor cells through cell experiments. Then siRNA constructs specific for PIAS3, PIAS3 overexpression plasmid and the mutation of the STAT3 Tyr705 residue were used to confirm the mechanism of Honokiol-induced apoptosis. Finally, we confrmed that honokiol can promote PIAS3 upregulation, in turn suppressing STAT3 Tyr705 phosphorylation through the in vivo and in vitro experiments. Honokiol was ultimately found to reduce tumor cell viability by promoting apoptosis through a mechanism dependent on the ability of Honokiol to promote PIAS3 upregulation and the selective inhibition of p-STAT3 (Tyr705) without affecting p-STAT3 (Ser727) or p-STAT1 (Tyr701) levels. PIAS3 knockdown and overexpression in tumor cells altered STAT3 activation and associated DNA binding activity through the control of Tyr705 phosphorylation via PIAS3-STAT3 complex formation, ultimately shaping Honokiol-induced tumor cell apoptosis. Honokiol was also confirmed to significantly prolong the survival of mice bearing xenograft tumors in a PIAS3-dependent fashion. Together, these findings highlight a novel pathway through which Honokiol can promote PIAS3 upregulation, in turn suppressing STAT3 Tyr705 phosphorylation and promoting the apoptotic death of tumor cells.

Biomimetic black phosphorus quantum dots-based photothermal therapy combined with anti-PD-L1 treatment inhibits recurrence and metastasis in triple-negative breast cancer.

BACKGROUND: Triple-negative breast cancer (TNBC) is a highly aggressive malignant disease with a high rate of recurrence and metastasis, few effective treatment options and poor prognosis. Here, we designed and constructed a combined photothermal immunotherapy strategy based on cancer cell membrane-coated biomimetic black phosphorus quantum dots (BBPQDs) for tumor-targeted photothermal therapy and anti-PD-L1 mediated immunotherapy. RESULTS: BBPQDs have good photothermal conversion efficiency and can efficiently target tumor cells through homologous targeting and tumor homing. Under near infrared irradiation, we found that BBPQDs kill tumors directly through photothermal effects and induce dendritic cells maturation. In vivo studies have confirmed that the combined photothermal immunotherapy strategy displays a stronger antitumor activity than anti-PD-L1 monotherapy. In addition, BBPQDs-mediated photothermal therapy in combination with anti-PD-L1 treatment inhibit tumor recurrence and metastasis by reprograming the immunosuppressive tumor microenvironment into an immune-active microenvironment, and promoting the local and systemic antitumor immune response. We further found that the combined photothermal immunotherapy strategy can produce an immune memory effect against tumor rechallenge. CONCLUSIONS: This study provides a novel therapeutic strategy for inhibiting the recurrence and metastasis of TNBC, with broad application prospects.

A modified prognostic model in patients with diffuse large B-cell lymphoma treated with immunochemotherapy.

In the era of immunochemotherapy, the traditional international prognostic index (IPI) has partially lost its predictive value in diffuse large B-cell lymphoma (DLBCL) and the National Comprehensive Cancer Network-IPI (NCCN-IPI) is unable to effectively identify high-risk patients. Thus, the present study aimed to develop a modified prognostic model (M-PM) to identify high-risk patients that require aggressive treatment. The present study included 169 patients with newly diagnosed DLBCL treated with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (RCHOP) or RCHOP-like regimens, between 2011-2017. The results demonstrated that the risk discrimination was improved in the NCCN-IPI compared with the IPI, and patients were divided into four risk groups with a 5-year overall survival rate of 93.8, 76.5, 54.3 and 39.4%, respectively. However, the NCCN-IPI failed to identify the high-risk DLBCL population. The newly developed M-PM presented here included four parameters: Age (≥65 years), an elevated lactate dehydrogenase level, Eastern Cooperative Oncology Group score ≥2 and total metabolic tumor volume ≥300 cm3. The M-PM also divided patients into four risk groups that comprised 40.8, 23.1, 26.0 and 10.1% of the patients, and the 5-year survival rates of these groups were 92.4, 70.6, 52.3 and 24.5%, respectively. Taken together, the results of the present study demonstrated that the M-PM was more accurate compared with the IPI and the NCCN-IPI, which served as an effective tool for identifying patients with DLBCL at high risk of an adverse prognosis.

Upconverting and persistent luminescent nanocarriers for accurately imaging-guided photothermal therapy.

The fluorescence-guided photothermal therapy (FPTT) has great potential in cancer treatment. However, the conventional FPTT has to be stimulated by external light, which tends to increase background noise and leads to the inaccurate infrared light irradiation for PTT. In this study, upconverting and persistent luminescent nanocarriers (UPLNs) loaded mesoporous silica nanoparticles (UPLNs@mSiO2) were first designed to solve the problem mentioned above. The UPLNs cores can effectively reduce the short-lived autofluorescence interference by exerting the delay time between signal acquisition and pulsed excitation light. For testing the luminescence properties, the indotcyanine green (ICG) as photothermal agent was encapsulated into the UPLNs@mSiO2. The experimental results showed that the UPLNs@mSiO2 nanoparticles could significantly reduce the short-lived autofluorescence interference and improve signal-to-noise ratio during FPTT. Our data suggest that UPLNs@mSiO2 may be a promising tool for improving the accuracy of PTT in vivo.