Basic & Clinical Pharmacology & Toxicology

Small‐molecule inhibitor HI‐TOPK‐032 improves NK‐92MI cell infiltration into ovarian tumours

AbstractThe effectiveness of natural killer (NK) cells transferred adoptively in combating solid tumours is limited by challenges such as their difficulty in penetrating tumours from the bloodstream and maintaining viability without the support of interleukin‐2 (IL‐2). Genetically modified NK‐92MI cells, which can release IL‐2 to sustain their viability, have been identified as a promising alternative. This adaptation addresses the negative consequences of systemic IL‐2 administration. The role of PSD‐95/discs large/ZO‐1 (PDZ)‐binding kinase (PBK) in cancer development is recognized, but its effects on immunity are not fully understood. This study explores how PBK expression influences the ability of NK‐92MI cells to infiltrate ovarian tumours. Elevated levels of PBK expression have been found in various cancers, including ovarian cancer (OV), with analyses showing higher PBK mRNA levels in tumour tissues compared to normal ones. Immunohistochemistry has confirmed increased PBK expression in OV tissues. Investigations into PBK's role in immune regulation reveal its association with immune cell infiltration, indicating a potentially compromised immune environment in OV with high PBK expression. The small‐molecule inhibitor HI‐TOPK‐032, which inhibits PBK, enhances the cytotoxicity of NK‐92MI cells toward OV cells. It increases the production of interferon‐γ and tumour necrosis factor‐α, reduces apoptosis and encourages cell proliferation. Mechanistic studies showed that contact with OV cells treated with HI‐TOPK‐032 upregulates CD107a on NK‐92 cells. In vivo studies demonstrated that HI‐TOPK‐032 improves the antitumour effects of NK‐92MI cells in OVCAR3Luc xenografts, extending survival without significant side effects. Safety assessments in mice confirm HI‐TOPK‐032's favourable safety profile, highlighting its potential as a viable antitumour therapy. These results suggest that combining NK‐92MI cells with HI‐TOPK‐032 enhances antitumour effectiveness against OV, indicating a promising, safe and effective treatment strategy that warrants further clinical investigation.

Xiao‐Jie‐An Capsule Alleviates Uterine Fibroids by Modulating Oestrogen–Progesterone Balance and Reducing Inflammatory Response

ABSTRACTUterine fibroids (UF) are benign tumours composed of smooth muscle cells and fibrous connective tissue. UF are common among women aged 30–50 years and often present with symptoms such as anaemia, pelvic pain and bladder dysfunction. Xiao‐Jie‐An Capsule (XJA), a traditional Chinese medicine formula, has been clinically used to treat UF. However, the underlying mechanisms of its efficacy remain unclear. The aim of this study was to determine the therapeutic effect of XJA and related mechanisms in a UF rat model. The experimental results showed that XJA significantly alleviated abnormalities in uterine morphology, tissue structure and purulent discharge in the UF rats. XJA also reduced serum oestrogen and progesterone in UF rats. Moreover, XJA decreased blood pro‐inflammatory factors in UF rats by modulating the TLR4/NF‐κB pathway. Western blotting and immunohistochemistry analyses revealed that XJA decreased the expression of Bcl‐2, PCNA and Ki67 while increasing the expression of Bax, indicating its role in inhibiting cell proliferation and promoting apoptosis. Additionally, XJA exhibited immunomodulation in UF rats. In summary, our study suggests that XJA alleviates UF by multiple targets and mechanisms, such as restoring the oestrogen–progesterone balance, reducing inflammation, inhibiting cell proliferation, inducing apoptosis and regulating immune function.

Toxicity and therapy outcome associations in LIG3, SLCO1B3, ABCB1, OPRM1 and GSTP1 in high‐grade serous ovarian cancer

AbstractAdverse effects are the major limiting factors in combinatorial chemotherapies. To identify genetic associations in ovarian cancer chemotherapy‐induced toxicities and therapy outcomes, we examined a cohort of 101 patients receiving carboplatin‐paclitaxel treatment with advanced high‐grade serous ovarian cancers. Based on literature and database searches, we selected 19 candidate polymorphisms, designed a multiplex single nucleotide polymorphism‐genotyping assay and applied Cox regression analysis, case–control association statistics and the log‐rank Mantel−Cox test. In the Cox regression analysis, the SLCO1B3 rs1052536 AA‐genotype was associated with a reduced risk of any severe toxicity (hazard ratio = 0.35, p = 0.023). In chi‐square allelic test, the LIG3 rs1052536 T‐allele was associated with an increased risk of neuropathy (odds ratio [OR] = 2.79, p = 0.031) and GSTP1 rs1695 G allele with a poorer response in the first‐line chemotherapy (OR = 2.65, p = 0.026). In Kaplan–Meier survival analysis, ABCB1 rs2032582 TT‐genotype was associated with shorter overall survival (uncorrected p = 0.025) and OPRM1 rs544093 GG and GT genotypes with shorter platinum‐free interval (uncorrected p = 0.027) and progression‐free survival (uncorrected p = 0.012). Results suggest that SLCO1B3 and LIG3 variants are associated with the risk of adverse effects in patients receiving carboplatin‐paclitaxel treatment, the GSTP1 variant may affect the treatment response and ABCB1 and OPRM1 variants may influence the prognosis.

Bufalin inhibits ovarian carcinoma via targeting mTOR/HIF‐α pathway

AbstractOvarian cancer is a severe health threat for women with increased incidence and stymied development in diagnosis and therapy. Drug resistance is still a big challenge. Bufalin is a multi‐functional steroid‐like compound extracted from natural product Chansu and has been tested as antitumour agent recently. The application and mechanism of bufalin in ovarian cancer remain unclear yet. Bufalin was first examined in ovarian epithelial cancer cell as well as primary ovarian tissue to evaluate its inhibitory activity in cell growth and migration, followed by the validation in xenograft tumour model and the patient samples. Bufalin is well tolerated by normal ovarian tissue at up to 40 μM and suppresses the cell growth and migration at 10 μM and xenograft tumour growth at 0.1mg/kg dosage. Bufalin inhibits the mammalian target of rapamycin (mTOR) activation and subsequently decreases hypoxia‐induced factor 1 alpha (HIF‐1α) level. Overexpression of HIF‐1α could abolish the pro‐apoptotic and antimigration activity of bufalin in cell culture. Strikingly, low HIF‐1α level was correlated with improved responsiveness to cisplatin treatment in ovarian cancer patients. Bufalin was a potent inhibitor of cell growth and migration in ovarian cancer cells through suppression of mTOR activation and HIF‐1α induction. Bufalin could be used to enhance the efficacy of cisplatin in ovarian cancer patients.