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Patients with bladder cancer (BCa) frequently acquires resistance to platinum-based chemotherapy, particularly cisplatin. This study centered on the mechanism of cisplatin resistance in BCa and highlighted the pivotal role of lactylation in driving this phenomenon. Utilizing single-cell RNA sequencing, we delineated the single-cell landscape of Bca, pinpointing a distinctive subset of BCa cells that exhibit marked resistance to cisplatin with association with glycolysis metabolism. Notably, we observed that H3 lysine 18 lactylation (H3K18la) plays a crucial role in activating the transcription of target genes by enriching in their promoter regions. Targeted inhibition of H3K18la effectively restored cisplatin sensitivity in these cisplatin-resistant epithelial cells. Furthermore, H3K18la-driven key transcription factors YBX1 and YY1 promote cisplatin resistance in BCa. These findings enhance our understanding of the mechanisms underlying cisplatin resistance, offering valuable insights for identifying novel intervention targets to overcome drug resistance in Bca., Competing Interests: Declaration of Competing Interest The authors have declared that no conflict of interest exists., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Refractoriness to conventional chemotherapy is a major challenge in the treatment of advanced ovarian cancer (OC). There is increasing evidence that mitochondrial priming correlates with cisplatin response in various cancers. Notably, Bim and Bid, two of the proapoptotic BH3-only proteins, are recognized as the most effective inducers of mitochondrial priming in OC. In this study, we constructed two tumor-specific oncolytic adenoviruses (Ads) coding for Bim (Ad-Bim) or truncated Bid (Ad-tBid), respectively, and performed gain-of-function assays in nine OC cell lines. Ad-tBid exhibited significant antitumor efficacy than the controls. On addition of Ad-tBid pretreatment, mito-primed cells displayed more sensitivity to cisplatin both in vitro and ex vivo . We also found that Ad-tBid induced mitochondrial apoptosis in a Bak-dependent manner. Furthermore, a combined cisplatin plus Ad-tBid therapy markedly inhibited tumor growth in a subcutaneous xenotransplanted tumor model. In mice bearing peritoneal disseminated OC, intraperitoneal administration of Ad-tBid potentiated the antitumor effect of cisplatin. Our findings suggest that Ad-tBid enhances cisplatin response in OC cells, establishing the potential treatment of advanced OC via a combination of cisplatin and Ad-tBid.

The blood-brain barrier (BBB) protects the central nervous system from external insults by limiting substance diffusion through the endothelial interface. The presence of the BBB makes drug delivery in neurological disorders very challenging. Cisplatin has been shown to be cytotoxic to glioma cells, but substantial limitations exist in its clinical applications due to difficulties in penetration across the BBB. Here, we show that L-borneol, a messenger drug widely used in traditional Chinese medicine, can induce transient disruption of the BBB after 20 min of oral administration. The permeability of the BBB began to recover within 1 h of the administration of L-borneol. Different dosages of L-borneol (100, 150, 300, 600, and 900 mg/kg) could induce significant Evans blue leakage (P<0.05). Oral administration of L-borneol elevated cisplatin concentrations in peritumoral tissue (1.24±0.12 μg/g) and tumor loci (1.41±0.13 μg/g), compared with those in the paraffin control (0.88±0.10 and 0.92±0.15 μg/g, respectively) (P<0.05). Furthermore, we found that the median survival period of tumor-bearing mice was significantly higher in the cisplatin plus L-borneol group (24.0±4.9 days) than in the cisplatin plus vehicle group (19.3±3.9 days) (P<0.05). The neurological deficits were more severe in the vehicle and cisplatin plus vehicle groups at 14 and 21 days after implantation of intracranial glioma cells than in the cisplatin plus L-borneol group. In conclusion, our results indicate that the transient opening of the BBB induced by L-borneol could enhance cisplatin accumulation within the glioma tissue and improve the survival of tumor-bearing mice.

The liver is normally the major site of glucose metabolism in intact organisms and the most important target organ for the action of insulin. It has been widely accepted that insulin resistance (IR) is closely associated with postoperative recurrence of hepatocellular carcinoma (HCC). However, the relationship between IR and drug resistance in liver cancer cells is unclear. In the present study, IR was induced in HepG2 cells via incubation with a high concentration of insulin. Once the insulin-resistant cell line was established, the instability of HepG2/ IR cells was further tested via incubation in insulin-free medium for another 72h. Afterwards, the biological effects of insulin resistance on adhesion, migration, invasion and sensitivity to cis-platinum (DDP) of cells were determined. The results indicated that glucose consumption was reduced in insulin-resistant cells. In addition, the expression of the insulin receptor and glucose transportor-2 was downregulated. Furthermore, HepG2/IR cells displayed markedly enhanced adhesion, migration, and invasion. Most importantly, these cells exhibited a lower sensitivity to DDP. By contrast, HepG2/IR cells exhibited decreased adhesion and invasion after treatment with the insulin sensitizer pioglitazone hydrochloride. The results suggest that IR is closely related to drug resistance as well as adhesion, migration, and invasion in HepG2 cells. These findings may help explain the clinical observation of limited efficacy for chemotherapy on a background of IR, which promotes the invasion and migration of cancer cells.

The aim of the present study was to investigate the role of Stat3 in cisplatin resistant ovarian cancer. It was first demonstrated that higher activated Stat3 was detected in cisplatin-resistant ovarian cancer cell lines. To provide evidence that supported the hypothesis that phosphorylated-Stat3 expression may promote cisplatin resistance, ectopic Stat3 was expressed by IL-6 stimulation that partially abrogates Stat3, as opposed to the knock-down of Stat3 by specific siRNA that restores cisplatin sensitivity against ovarian cancer cells. This hypothesis was further confirmed by clinical tumor specimens of ovarian cancer obtained from patients with cisplatin-resistance. Based on these premises, Stattic, an effective small molecular inhibitor of Stat3, was used to inhibit Stat3 activation. The data presented here show that Stattic restored the sensitivity to cisplatin in chemoresistant ovarian cancer by significant reductions in the expression of the anti-apoptosis protein Bcl-2, Bcl-XL, Survivin protein and phosphorylated-Akt levels. Consistent with these observations, this experiment demonstrated the first evidence of Stattic circumvented cisplatin resistance of orthotopic xenograft ovarian cancer in vivo. Altogether, these findings emphasize the importance of Stat3 in cisplatin resistance in ovarian cancer and provide a further impetus to clinically evaluate biological modifiers that may circumvent cisplatin resistance in patients with chemoresistant ovarian cancer., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Human epididymis protein 4 (HE4) is a glycoprotein secreted by epithelial ovarian cancer (EOC) cells and is a novel and specific biomarker for diagnosing and prognosing EOC. Previous studies have shown that overexpression of HE4 is correlated with EOC tumorigenesis and chemoresistance. However, less has been reported regarding the direct effect of the secreted HE4 protein as an autocrine factor in EOC cells. Here, we investigated the molecular mechanism of the secretory form of HE4 on the growth of EOC cells by applying nanobodies with a targeted interaction of free HE4. Three anti-HE4 nanobodies were selected from an immune library by phage display. HE4 secreted by serum-free cultured OVCAR3 cells increased and was effectively neutralized by anti-HE4 nanobodies, which inhibited cell viability. Treatment with the anti-HE4 nanobody 1G8 decreased Bcl-2 expression and increased BAX, cleaved PARP, and p53 levels, resulting in apoptosis of OVCAR3 cells. Moreover, 1G8 significantly improved the cisplatin response of OVCAR3 cells. Our data suggest that secretory HE4 played a novel pro-survival autocrine role and was a target of the anti-HE4 nanobody to improve the therapeutic effects of cisplatin-based chemotherapy. [ABSTRACT FROM AUTHOR]

Cisplatin is one of the most used first-line anticancer drugs for various solid tumor therapies. However, cisplatin-based chemotherapy can induce tumor cells to secrete excessive prostaglandin E2 (PGE2) catalyzed by cyclooxygenase-2 (COX-2), which, in turn, counteracts its chemotherapeutic effect and further accelerates tumor metastasis. Here, we report a carrier-free self-delivered nanoprodrug based on platinum (II) coordination bonding coupled with tolfenamic acid (Tolf) (named Tolfplatin). Tolfplatin can spontaneously assemble into uniformly sized nanoparticles (NPs) with a high drug-loading capacity. Compared with cisplatin, Tolfplatin NPs can facilitate cellular uptake, significantly decrease PGE2 secretion by COX-2 inhibition, which further downregulate tumorous anti-apoptotic and metastasis-associated proteins, thereby efficiently inducing apoptotic cell death and significantly inhibit tumor metastasis in vitro and in vivo. Therefore, as the carrier-free nanoprodrug, Tolfplatin NPs are promising anti-tumoral agents to inhibit tumor proliferation and metastasis by enriching the function and promoting the anti-tumor activity of cisplatin. Unlabelled Image • An anti-inflammatory dual-functional anticancer prodrug (named Tolfplatin) was synthesized through platinum (II) coupled with Tolfenamic acid by coordination bonding. • Tolfplatin can self-assemble into uniformly sized nanoparticles (NPs) with a high drug-loading capacity. • Tolfplatin NPs not only functions as anti-tumor drug but also exerts the anti-inflammatory as well as anti-metastasis effect. • Tolfplatin NPs can significantly prolong the survival time of tumor-bearing mice compared with cisplatin. [ABSTRACT FROM AUTHOR]