<p>Nanoparticle BAF312@CaP-NP Overcomes Sphingosine-1-Phosphate Receptor-1-Mediated Chemoresistance Through Inhibiting S1PR1/P-STAT3 Axis in Ovarian Carcinoma</p>

Abstract

Purpose Platinum/paclitaxel-based chemotherapy is the strategy for ovarian cancer, but chemoresistance, inherent or acquired, occurs and hinders therapy. Therefore, further understanding of the mechanisms of drug resistance and adoption of novel therapeutic strategies are urgently needed. Methods In this study, we report that sphingosine-1-phosphate receptor-1 (S1PR1)-mediated chemoresistance for ovarian cancer. Then we developed nanoparticles with a hydrophilic PEG2000 chain and a hydrophobic DSPE and biodegradable CaP (calcium ions and phosphate ions) shell with pH sensitivity as a delivery system (CaP-NPs) to carry BAF312, a selective antagonist of S1PR1 (BAF312@CaP-NPs), to overcome the cisplatin (DDP) resistance of the ovarian cancer cell line SKOV3DR. Results We found that S1PR1 affected acquired chemoresistance in ovarian cancer by increasing the phosphorylated-signal transduction and activators of transcription 3 (P-STAT3) level. The mean size and zeta potential of BAF312@CaP-NPs were 116 ± 4.341 nm and −9.67 ± 0.935 mV, respectively. The incorporation efficiency for BAF312 in the CaP-NPs was 76.1%. The small size of the nanoparticles elevated their enrichment in the tumor, and the degradable CaP shell with smart pH sensitivity of the BAF312@CaP-NPs ensured the release of BAF312 in the acidic tumor niche. BAF312@CaP-NPs caused substantial cytotoxicity in DDP-resistant ovarian cancer cells by downregulating S1PR1 and P-STAT3 levels. Conclusion We found that BAF312@CaP-NPs act as an effective and selective delivery system for overcoming S1PR1-mediated chemoresistance in ovarian carcinoma by inhibiting S1PR1 and P-STAT3.

Pre-existing cancer cells and induced fibroblasts are key cells for early chemoresistance in ovarian cancer

“…Another subnetwork was formed by cancer-related genes such as STAT3 and MYC. The overexpression of both genes have well been linked to chemoresistance in ovarian cancer (47,48). Genes within these subnetworks could have critical roles in chemoresistance and are good candidate targets.…”

MiR-4284 inhibits sensitivity to paclitaxel in human ovarian carcinoma SKOV3ip1 and HeyA8 cells by targeting DMC1

“…The majority of OC cases are diagnosed when becoming advanced and the five-year survival rate is only approximately 20% [2,3]. For the treatment of advanced OC, paclitaxel chemotherapy is an approach widely adopted by doctors [4]. Paclitaxel is a microtubule-stabilizing drug with the capability of inducing mitotic arrest, thereby suppressing tumor growth [5].…”

CB[8]- and triarylboron-based supramolecular organic framework for microRNA detection, tumor-targeted drug delivery, and photodynamic therapy

“…18 Thus, miRNAs are important biomarkers for cancer diagnosis and prognosis. 19,20 Many malignancies, such as breast cancer, pancreatic cancer, brain tumors, leukemia, and colorectal cancer, show high miRNA 21 (miR-21) expression levels. 21 Therefore, constructing a SOF that can be disassembled by miRNAs to achieve effective detection of miRNA, selective imaging of tumor cells, or release of drug at the tumor site would be meaningful.…”

“…[22][23][24] However, the most obvious disadvantage of chemotherapeutic drugs is drug resistance, which reduces their therapeutic efficacy. [25][26][27][28][29] Therefore, combining chemotherapy with other treatments may be a feasible way to overcome drug resistance. As a relatively new treatment method, photodynamic therapy (PDT) has received widespread attention owing to its non-invasive nature and spatiotemporal selectivity, because of which a more precise and effective therapy can be realized by inducing the apoptosis of cancer cells in the presence of photosensitive components under light.…”