Cisplatin-resistant Cancer Cells Research Articles

Jolkinolide B synergistically potentiates the antitumor activity of GPX4 inhibitors via inhibiting TrxR1 in cisplatin-resistant bladder cancer cells

Glutathione peroxidase 4 (GPX4) is a promising anticancer therapeutic target; however, the application of GPX4 inhibitors (GPX4i) is limited owing to intrinsic or acquired drug resistance. Hence, understanding the mechanisms underlying drug resistance and discovering molecules that can overcome drug resistance are crucial. Herein, we demonstrated that GPX4i killed bladder cancer cells by inducing lipid reactive oxygen species-mediated ferroptosis and apoptosis, and cisplatin-resistant bladder cancer cells were also resistant to GPX4i, representing a higher half-maximal inhibitory concentration value than that of parent bladder cancer cells. In addition, thioredoxin reductase 1 (TrxR1) overexpression was responsible for GPX4i resistance in cisplatin-resistant bladder cancer cells, and inhibiting TrxR1 restored the sensitivity of these cells to GPX4i. In vitro and in vivo studies revealed that Jolkinolide B (JB), a natural diterpenoid and previously identified as a TrxR1 inhibitor, potentiated the antiproliferative efficacy of GPX4i (RSL3 and ML162) against cisplatin-resistant bladder cancer cells. Furthermore, GPX4 knockdown and inhibition could augment JB-induced paraptosis and apoptosis. Our results suggest that inhibiting TrxR1 can effectively improve GPX4 inhibition-based anticancer therapy. A combination of JB and GPX4i, which is well-tolerated and has several anticancer mechanisms, may serve as a promising therapy for treating bladder cancer.

Expression of human dCTP pyrophosphatase 1 (DCTPP1) and its association with cisplatin resistance characteristics in ovarian cancer.

Cisplatin (DDP) resistance is a major challenge in treating ovarian cancer patients. A recently discovered enzyme called dCTP pyrophosphatase 1 (DCTPP1) has been implicated in regulating cancer characteristics, including drug responses. In this study, we aimed to understand the role of DCTPP1 in cancer progression and cisplatin response. Using publicly available databases, we analysed the expression and clinical significance of DCTPP1 in ovarian cancer. Our bioinformatics analysis confirmed that DCTPP1 is significantly overexpressed in ovarian cancer and is closely associated with tumour progression and poor prognosis after cisplatin treatment. We also found that DCTPP1 located in oxidoreductase complex and may be involved in various biological processes related to cisplatin resistance, including pyrimidine nucleotide metabolism, the P53 signalling pathway and cell cycle signalling pathways. We observed higher expression of DCTPP1 in cisplatin-resistant cells (SKOV3/DDP) and samples compared to their sensitive counterparts. Additionally, we found that DCTPP1 expression was only enhanced in SKOV3/S cells when treated with cisplatin, indicating different expression patterns of DCTPP1 in cisplatin-sensitive and cisplatin-resistant cancer cells. Our study further supports the notion that cisplatin induces intracellular reactive oxygen species (ROS) and triggers cancer cell death through excessive oxidative stress. Knocking out DCTPP1 reversed the drug resistance of ovarian cancer cells by enhancing the intracellular antioxidant stress response and accumulating ROS. Based on our research findings, we conclude that DCTPP1 has prognostic value for ovarian cancer patients, and targeting DCTPP1 may be clinically significant in overcoming cisplatin resistance in ovarian cancer.

Plasmonic laser-responsive BioDissolve 3D-printed graphene@cisplatin-implant for prevention of post-surgical relapse of oral cancer

The development of chemoresistance is a major obstacle in post-surgical adjuvant therapy of cancer, leading to cancer cell survival, recurrence, and metastasis. This study reports a 3D-printed plasmonic implant developed for the post-surgical adjuvant therapy of cisplatin-resistant cancer cells to prevent relapse. The implant was printed using optimized biomaterial ink containing biodegradable polymers [poly(L-lactide) and hydroxypropyl methylcellulose] blended suitably with laser-responsive graphene and chemo drug (Cisplatin). The irradiation of scar-driven 3D-printed implant with a laser stimulates graphene to generate a series of hyperthermia events leading to photothermolysis of cisplatin-resistant cancer cells under the combined influence of sustained cisplatin release. The developed personalized implant offers pH-responsive sustained drug release for 28 days. The implant exhibited acceptable biophysical properties (Tensile strength: 3.99 ± 0.15 MPa; modulus: 81 ± 9.58 MPa; thickness: 110 μm). The 3D-printed implant effectively reverses the chemoresistance in cisplatin-resistant 3D spheroid tumor models. Cytotoxicity assay performed using cisplatin-resistant (CisR) cell line revealed that the cell viability was reduced to 39.80 ± 0.68 % from 61.37 ± 0.98 % in CisR tumor spheroids on combined chemo-photothermal therapy. The combination therapy reduced the IC50 value from 71.05 μM to 48.73 μM in CisR spheroids. Apoptosis assay revealed an increase in the population of apoptotic cells (35.45 ± 1.56 % →52.53 ± 2.30 %) on combination therapy. A similar trend was observed in gene expression analysis, where the expression of pro-apoptotic genes Caspase 3 (3.73 ± 0.04 fold) and Bcl-2-associated X protein (BAX) (3.35 ± 0.02 fold) was increased on combination therapy. This 3D-printed, biodegradable implant with chemo-combined thermal ablating potential may provide a promising approach for the adjuvant treatment of resistant cancer.

Role and mechanism of COL3A1 in regulating the growth, metastasis, and drug sensitivity in cisplatin-resistant non-small cell lung cancer cells

ABSTRACT Non-small cell lung cancer (NSCLC) is among the most difficult malignancies to treat. Type III collagen (COL3A1) can affect the progression and chemoresistance development of NSCLC. We herein explored the mechanism that drives COL3A1 dysregulation in NSCLC. Potential RNA-binding proteins (RBPs) and transcription factors (TFs) that could bind to COL3A1 were searched by bioinformatics. mRNA expression was detected by quantitative PCR. Protein expression was evaluated using immunoblotting and immunohistochemistry. The effects of the variables were assessed by gauging cell growth, invasiveness, migratory capacity, apoptosis, and cisplatin (DDP) sensitivity. The direct YY1/COL3A1 relationship was confirmed by ChIP and luciferase reporter experiments. Xenograft experiments were done to examine COL3A1’s function in DDP efficacy. COL3A1 showed enhanced expression in DDP-resistant NSCLC. In H460/DDP and A549/DDP cells, downregulation of COL3A1 exerted inhibitory functions in cell growth, invasiveness, and migration, as well as promoting effects on cell DDP sensitivity and apoptosis. Mechanistically, ELAV-like RNA binding protein 1 (ELAVL1) enhanced the mRNA stability and expression of COL3A1, and Yin Yang 1 (YY1) promoted the transcription and expression of COL3A1. Furthermore, upregulation of COL3A1 reversed ELAVL1 inhibition- or YY1 deficiency-mediated functions in DDP-resistant NSCLC cells. Additionally, COL3A1 downregulation enhanced the anti-tumor efficacy of DDP in vivo. Our investigation demonstrates that COL3A1 upregulation, induced by both RBP ELAVL1 and TF YY1, exerts important functions in phenotypes of NSCLC cells with DDP resistance, offering an innovative opportunity in the treatment of drug-resistant NSCLC.

APLF facilitates interstrand DNA crosslink repair and replication fork protection to confer cisplatin resistance.

Replication stress converts the stalled forks into reversed forks, which is an important protection mechanism to prevent fork degradation and collapse into poisonous DNA double-strand breaks (DSBs). Paradoxically, the mechanism also acts in cancer cells to contribute to chemoresistance against various DNA-damaging agents. PARP1 binds to and is activated by stalled forks to facilitate fork reversal. Aprataxin and polynucleotide kinase/phosphatase-like factor (APLF) binds to PARP1 through the poly(ADP-ribose) zinc finger (PBZ) domain and is known to be involved in non-homologous end joining (NHEJ). Here, we identify a novel function of APLF involved in interstrand DNA crosslink (ICL) repair and fork protection. We demonstrate that PARP1 activity facilitates the APLF recruitment to stalled forks, enabling the FANCD2 recruitment to stalled forks. The depletion of APLF sensitizes cells to cisplatin, impairs ICL repair, reduces the FANCD2 recruitment to stalled forks, and results in nascent DNA degradation by MRE11 nucleases. Additionally, cisplatin-resistant cancer cells show high levels of APLF and homologous recombination-related gene expression. The depletion of APLF sensitizes cells to cisplatin and results in fork instability. Our results reveal the novel function of APLF to facilitate ICL repair and fork protection, thereby contributing to cisplatin-resistant phenotypes of cancer cells.

USP28 promotes tumorigenesis and cisplatin resistance by deubiquitinating MAST1 protein in cancer cells

Cisplatin is a chemotherapy drug that causes a plethora of DNA lesions and inhibits DNA transcription and replication, resulting in the induction of apoptosis in cancer cells. However, over time, patients develop resistance to cisplatin due to repeated treatment and thus the treatment efficacy is limited. Therefore, identifying an alternative therapeutic strategy combining cisplatin treatment along with targeting factors that drive cisplatin resistance is needed. CRISPR/Cas9 system-based genome-wide screening for the deubiquitinating enzyme (DUB) subfamily identified USP28 as a potential DUB that governs cisplatin resistance. USP28 regulates the protein level of microtubule-associated serine/threonine kinase 1 (MAST1), a common kinase whose expression is elevated in several cisplatin-resistant cancer cells. The expression level and protein turnover of MAST1 is a major factor driving cisplatin resistance in many cancer types. Here we report that the USP28 interacts and extends the half-life of MAST1 protein by its deubiquitinating activity. The expression pattern of USP28 and MAST1 showed a positive correlation across a panel of tested cancer cell lines and human clinical tissues. Additionally, CRISPR/Cas9-mediated gene knockout of USP28 in A549 and NCI-H1299 cells blocked MAST1-driven cisplatin resistance, resulting in suppressed cell proliferation, colony formation ability, migration and invasion in vitro. Finally, loss of USP28 destabilized MAST1 protein and attenuated tumor growth by sensitizing cells to cisplatin treatment in mouse xenograft model. We envision that targeting the USP28-MAST1 axis along with cisplatin treatment might be an alternative therapeutic strategy to overcome cisplatin resistance in cancer patients.

Platinum(0)-η2-1,2-(E)ditosylethene Complexes Bearing Phosphine, Isocyanide and N-Heterocyclic Carbene Ligands: Synthesis and Cytotoxicity towards Ovarian and Breast Cancer Cells.

A wide range of platinum(0)-η2-(E)-1,2-ditosylethene complexes bearing isocyanide, phosphine and N-heterocyclic carbene ancillary ligands have been prepared with high yields and selectivity. All the novel products underwent thorough characterization using spectroscopic techniques, including NMR and FT-IR analyses. Additionally, for some compounds, the solid-state structures were elucidated through X-ray diffractometry. The synthesized complexes were successively evaluated for their potential as anticancer agents against two ovarian cancer cell lines (A2780 and A2780cis) and one breast cancer cell line (MDA-MB-231). The majority of the compounds displayed promising cytotoxicity within the micromolar range against A2780 and MDA-MB-231 cells, with IC50 values comparable to or even surpassing those of cisplatin. However, only a subset of compounds was cytotoxic against cisplatin-resistant cancer cells (A2780cis). Furthermore, the assessment of antiproliferative activity on MRC-5 normal cells revealed certain compounds to exhibit in vitro selectivity. Notably, complexes 3d, 6a and 6b showed low cytotoxicity towards normal cells (IC50 > 100 µM) while concurrently displaying potent cytotoxicity against cancer cells.

MAP4K4 and WT1 mediate SOX6-induced cellular senescence by synergistically activating the ATF2-TGFβ2-Smad2/3 signaling pathway in cervical cancer.

SRY-box transcription factor 6 (SOX6) is a member of the SOX gene family and inhibits the proliferation of cervical cancer cells by inducing cell cycle arrest. However, the final cell fate and significance of these cell-cycle-arrested cervical cancer cells induced by SOX6 remains unclear. Here, we report that SOX6 inhibits the proliferation of cervical cancer cells by inducing cellular senescence, which is mainly mediated by promoting transforming growth factor beta 2 (TGFB2) gene expression and subsequently activating the TGFβ2-Smad2/3-p53-p21WAF1/CIP1 -Rb pathway. SOX6 promotes TGFB2 gene expression through the MAP4K4-MAPK (JNK/ERK/p38)-ATF2 and WT1-ATF2 pathways, which is dependent on its high-mobility group (HMG) domain. In addition, the SOX6-induced senescent cervical cancer cells are resistant to cisplatin treatment. ABT-263 (navitoclax) and ABT-199 (venetoclax), two classic senolytics, can specifically eliminate the SOX6-induced senescent cervical cancer cells, and thus significantly improve the chemosensitivity of cisplatin-resistant cervical cancer cells. This study uncovers that the MAP4K4/WT1-ATF2-TGFβ2 axis mediates SOX6-induced cellular senescence, which is a promising therapeutic target in improving the chemosensitivity of cervical cancer.

A Nanoscale Trans-Platinum(II)-Based Supramolecular Coordination Self-Assembly with a Distinct Anticancer Mechanism.

Drug resistance significantly hampers the clinical application of existing platinum-based anticancer drugs. New platinum medications that possess distinct mechanisms of action are highly desired for the treatment of Pt-resistant cancers. Herein, a nanoscale trans-platinum(II)-based supramolecular coordination self-assembly (Pt-TCPP-BA) is prepared via using trans-[PtCl2 (pyridine)(NH3 )] (transpyroplatin), tetracarboxylporphyrin (TCPP), and benzoic acid (BA) as building blocks to combat drug resistance in platinum-based chemotherapy. Mechanistic studies indicate that Pt-TCPP-BA shows a hydrogen-peroxide-responsive dissociation behavior along with the generation of bioactive trans-Pt(II) and TCPP-Pt species. Different from cisplatin, these degradation products interact with DNA via interstrand cross-links and small groove binding, and induce significant upregulation of cell-death-related proteins such as p53, cleaved caspase 3, p21, and phosphorylated H2A histone family member X in cisplatin-resistant cancer cells. As a result, Pt-TCPP-BA exhibits potent killing effects against Pt-resistant tumors both in vitro and in vivo. Overall, this work not only provides a new platinum drug for combating drug-resistant cancer but also offers a new paradigm for the development of platinum-based supramolecular anticancer drugs.

Plasma-Activated Media Produced by a Microwave-Excited Atmospheric Pressure Plasma Jet Is Effective against Cisplatin-Resistant Human Bladder Cancer Cells In Vitro.

Media exposed to atmospheric pressure plasma (APP) produce reactive oxygen and nitrogen species (RONS), with hydrogen peroxide (H2O2), nitrite (NO2-), and nitrate (NO3-) being among the most detected species due to their relatively long lifetime. In this study, a standardized microwave-excited (ME) APP jet (APPJ) source was employed to produce gaseous RONS to treat liquid samples. The source was a commercially available plasma jet, which generated argon plasma utilizing a coaxial transmission line resonator at the operating frequency of 2.45 GHz. An ultraviolet-visible spectrophotometer was used to measure the concentrations of H2O2 and NO3- in plasma-activated media (PAM). Three different types of media (deionized water, Hank's balanced salt solution, and cell culture solution Dulbecco's modified eagles medium [DMEM]) were utilized as liquid samples. Among these media, the plasma-treated DMEM was observed to have the highest levels of H2O2 and NO3-. Subsequently, the feasibility of using argon ME-APPJ-activated DMEM (PAM) as an adjuvant to enhance the therapeutic effects of cisplatin on human bladder cancer cells (T-24) was investigated. Various cancer cell lines, including T-24 cells, treated with PAM were observed in vitro for changes in cell viability using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. A viability reduction was detected in the various cancer cells after incubation in PAM. Furthermore, the study's results revealed that PAM was effective against cisplatin-resistant T-24 cells in vitro. In addition, a possible connection between HER expression and cell viability was sketched.

The E3 ubiquitin ligase Itch regulates death receptor and cholesterol trafficking to affect TRAIL-mediated apoptosis

The activation of apoptosis signalling by TRAIL (TNF-related apoptosis-inducing ligand) through receptor binding is a fundamental mechanism of cell death induction and is often perturbed in cancer cells to enhance their cell survival and treatment resistance. Ubiquitination plays an important role in the regulation of TRAIL-mediated apoptosis, and here we investigate the role of the E3 ubiquitin ligase Itch in TRAIL-mediated apoptosis in oesophageal cancer cells. Knockdown of Itch expression results in resistance to TRAIL-induced apoptosis, caspase-8 activation, Bid cleavage and also promotes cisplatin resistance. Whilst the assembly of the death-inducing signalling complex (DISC) at the plasma membrane is not perturbed relative to the control, TRAIL-R2 is mis-localised in the Itch-knockdown cells. Further, we observe significant changes to mitochondrial morphology alongside an increased cholesterol content. Mitochondrial cholesterol is recognised as an important anti-apoptotic agent in cancer. Cells treated with a drug that increases mitochondrial cholesterol levels, U18666A, shows a protection from TRAIL-induced apoptosis, reduced caspase-8 activation, Bid cleavage and cisplatin resistance. We demonstrate that Itch knockdown cells are less sensitive to a Bcl-2 inhibitor, show impaired activation of Bax, cytochrome c release and an enhanced stability of the cholesterol transfer protein STARD1. We identify a novel protein complex composed of Itch, the mitochondrial protein VDAC2 and STARD1. We propose a mechanism where Itch regulates the stability of STARD1. An increase in STARD1 expression enhances cholesterol import to mitochondria, which inhibits Bax activation and cytochrome c release. Many cancer types display high mitochondrial cholesterol levels, and oesophageal adenocarcinoma tumours show a correlation between chemotherapy resistance and STARD1 expression which is supported by our findings. This establishes an important role for Itch in regulation of extrinsic and intrinsic apoptosis, mitochondrial cholesterol levels and provides insight to mechanisms that contribute to TRAIL, Bcl-2 inhibitor and cisplatin resistance in cancer cells.

Histone acetylation: a key determinant of acquired cisplatin resistance in cancer

Cisplatin is an alkylating class of chemotherapeutic drugs used to treat cancer patients. However, cisplatin fails in long-term treatment, and drug resistance is the primary reason for tumor recurrence. Hence, understanding the mechanism of acquirement of chemoresistance is essential for developing novel combination therapeutic approaches. In this study, in vitro cisplatin-resistant cancer cell line models were developed. Gene ontology and GSEA of differentially expressed genes between parental and resistant cells suggest that PI3K-AKT signaling, central carbon metabolism, and epigenetic-associated phenomenon alter in cisplatin-resistant cells. Further, the data showed that increased glucose transport, alteration in the activity of histone-modifying enzymes, and acetyl-CoA levels in resistant cells paralleled an increase in global histone acetylation. Enrichment of histone acetylation on effectors of PI3K-AKT and glycolysis pathway provides evidence of epigenetic regulation of the key molecules in drug resistance. Moreover, cisplatin treatment to resistant cells showed no significant changes in histone acetylation marks since drug treatment alters cell epigenome. In continuation, targeting PI3K-AKT signaling and glycolysis leads to alteration in histone acetylation levels and re-sensitization of resistant cells to chemo-drug. The data provide evidence of histone acetylation's importance in regulating pathways and cisplatin-resistant cells' cell survival. Our study paves the way for new approaches for developing personalized therapies in affecting metabolic pathways and epigenetic changes to achieve better outcomes for targeting drug-resistant cells.

The ZuoJinWan formula inhibits glycolysis of cisplatin resistant gastric cancer cells via p53 acetylation

IntroductionGastric cancer is one of the common malignancies worldwide, and drug resistance is a major factor contributing to the difficulty of treatment in gastric cancer. Zuojinwan (ZJW) has been found to exhibit a certain inhibitory effect on tumor cells. However, the molecular mechanisms of ZJW reversing drug resistance in gastric cancer are still unclear. MethodHuman gastric cancer cisplatin-resistant cells SGC-7901/DDP and BGC-823/DDP were divided into control groups, DDP groups (10 μg/mL), 2-DG (5 mM) groups, and ZJW (50 μg/mL) combined with DDP (10 μg/mL) groups. After 48 h of culture, cell proliferation inhibition rate, glucose uptake rate, ATP, and lactate production were detected. Following lentiviral transfection to overexpress GLUT1 and HDAC1, western blot analysis was employed to examine the expression of HDAC1, P53, Ace-p53, and glucose metabolism-related proteins such as GLUT1, LDHA, HK II in the cells. ResultsThe combination of ZJW and DDP significantly inhibits the proliferation and glycolysis of cisplatin resistant gastric cancer cells. Compared with the DDP group, the combination of ZJW and DDP exhibited a higher inhibition rate (P < 0.01), accompanied by a reduction in the expression of HDAC1 and P53 proteins. ConclusionsZuojinwan can enhance the proliferation inhibition rate of SGC-7901/DDP and BGC-823/DDP cells, attenuate glycolysis, and reduce chemotherapy resistance. Its mechanism may be associated with the inhibition of HDAC1/P53 axis activity.

Therapeutic Potential of Regorafenib in Cisplatin-Resistant Bladder Cancer with High Epithelial-Mesenchymal Transition and Stemness Properties.

Bladder cancer is becoming one of the most common malignancies across the world. Although treatment strategy has been continuously improved, which has led to cisplatin-based chemotherapy becoming the standard medication, cancer recurrence and metastasis still occur in a high proportion of patients because of drug resistance. The high efficacy of regorafenib, a broad-spectrum kinase inhibitor, has been evidenced in treating a variety of advanced cancers. Hence, this study investigated whether regorafenib could also effectively antagonize the survival of cisplatin-resistant bladder cancer and elucidate the underlying mechanism. Two types of cisplatin-resistant bladder cancer cells, T24R1 and T24R2, were isolated from T24 cisplatin-sensitive bladder cancer cells. These cells were characterized, and T24R1- and T24R2-xenografted tumor mice were created to examine the therapeutic efficacy of regorafenib. T24R1 and T24R2 cells exhibited higher expression levels of epithelial-mesenchymal transition (EMT) and stemness markers compared to the T24 cells, and regorafenib could simultaneously inhibit the viability and the expression of EMT/stemness markers of both T24R1 and T24R2 cells. Moreover, regorafenib could efficiently arrest the cell cycle, promote apoptosis, and block the transmigration/migration capabilities of both types of cells. Finally, regorafenib could significantly antagonize the growth of T24R1- and T24R2-xenografted tumors in mice. These results demonstrated the therapeutic efficacy of regorafenib in cisplatin-resistant bladder cancers. This study, thus, provides more insights into the mechanism of action of regorafenib and demonstrates its great potential in the future treatment of cisplatin-resistant advanced bladder cancer patients.

Secreted frizzled-related protein 4 induces gastric cancer progression and resistance to cisplatin and oxaliplatin via β-catenin dysregulation

Introduction: Gastric cancer is the 5th most common cancer and 3rd leading cause of cancer-related death worldwide. There are three main ways to treat gastric cancer: surgical resection, radiation therapy, and drug therapy. Furthermore, combinations of two to three regimens can improve survival. However, the survival outcomes of chemotherapy in advanced gastric cancer patients are still unsatisfactory. Unfortunately, no widely useful biomarkers have been verified to predict the efficacy of chemotherapy for locally advanced gastric cancer. Methods: An MTT assay was used to determine the cell viability after cisplatin or oxaliplatin treatment. Western blotting and immunohistochemistry were utilized to examine the sFRP4 level and associated signaling pathways. Immunofluorescence staining was utilized to analyze the location of β-catenin. Colony formation and Transwell assays were used to analyze the functions related with cisplatin, oxaliplatin and sFRP4. Results: We have found that gastric cancer patients treated with combinations of 5-fluorouracil (5-FU) and cisplatin regimens have better survival rates than those treated with 5-FU-based chemotherapy alone. Secreted frizzled-related protein 4 (sFRP4) was selected as a potential target from stringent analysis and intersection of 5-FU and cisplatin resistance-related gene sets. sFRP4 was shown to be overexpressed in clinical gastric tumor tissues and positively correlated with a worse survival rate. In addition, sFRP4 and β-catenin were upregulated in cisplatin-resistant and oxaliplatin-resistant gastric cancer cells compared to parental cells. Immunofluorescence staining and nuclear fractionation showed that β-catenin translocated from the cytosol into the nucleus. Moreover, sFRP4 was detected in the conditioned medium of these resistant cells, which indicates that sFRP4 might have an extracellular role in chemotherapy resistance. Increased migration capacity and dysregulation of epithelial-mesenchymal transition-related markers, which might result from the dysregulation of sFRP4, were observed in cisplatin-resistant and oxaliplatin-resistant gastric cancer cells. Discussion/Conclusion: In summary, sFRP4 might play a critical role in resistance to cisplatin and oxaliplatin, cell metastasis and poor prognosis in gastric cancer via the Wnt-β-catenin pathway. Investigations of the molecular mechanism underlying sFRP4-modulated cancer progression and chemotherapeutic outcomes can provide additional therapeutic strategies for gastric cancer.

Z-Ligustilide Combined with Cisplatin Reduces PLPP1-Mediated Phospholipid Synthesis to Impair Cisplatin Resistance in Lung Cancer

Lung cancer is a malignant tumor with one of the highest morbidity and mortality rates in the world. Approximately 80–85% of lung cancer is diagnosed as non-small lung cancer (NSCLC), and its 5-year survival rate is only 21%. Cisplatin is a commonly used chemotherapy drug for the treatment of NSCLC. Its efficacy is often limited by the development of drug resistance after long-term treatment. Therefore, determining how to overcome cisplatin resistance, enhancing the sensitivity of cancer cells to cisplatin, and developing new therapeutic strategies are urgent clinical problems. Z-ligustilide is the main active ingredient of the Chinese medicine Angelica sinensis, and has anti-tumor activity. In the present study, we investigated the effect of the combination of Z-ligustilide and cisplatin (Z-ligustilide+cisplatin) on the resistance of cisplatin-resistant lung cancer cells and its mechanism of action. We found that Z-ligustilide+cisplatin decreased the cell viability, induced cell cycle arrest, and promoted the cell apoptosis of cisplatin-resistant lung cancer cells. Metabolomics combined with transcriptomics revealed that Z-ligustilide+cisplatin inhibited phospholipid synthesis by upregulating the expression of phospholipid phosphatase 1 (PLPP1). A further study showed that PLPP1 expression was positively correlated with good prognosis, whereas the knockdown of PLPP1 abolished the effects of Z-ligustilide+cisplatin on cell cycle and apoptosis. Specifically, Z-ligustilide+cisplatin inhibited the activation of protein kinase B (AKT) by reducing the levels of phosphatidylinositol 3,4,5-trisphosphate (PIP3). Z-ligustilide+cisplatin induced cell cycle arrest and promoted the cell apoptosis of cisplatin-resistant lung cancer cells by inhibiting PLPP1-mediated phospholipid synthesis. Our findings demonstrate that the combination of Z-Ligustilide and cisplatin is a promising approach to the chemotherapy of malignant tumors that are resistant to cisplatin.

Coexpression network analysis identified MT3 as a hub gene that promotes the chemoresistance of oral cancer by regulating the expression of YAP1

BackgroundOral cancer is considered one of the most malignant types of tumors and is known for its high likelihood of recurrence and metastasis. During clinical treatment, patients with oral cancer often develop resistance to chemotherapy, making the treatment process challenging. The purpose of this study was to investigate the genes related to chemotherapy resistance and their mechanisms in oral cancer patients.MethodsThe “limma” package was used to identify the differentially expressed genes between tumor and normal tissues from TCGA dataset. Subsequently, the “WGCNA” package was utilized to discover genes associated with chemoresistance. Cisplatin-resistant oral cancer cell lines were obtained through exposure to gradually increasing doses of cisplatin. SiRNA was used to knock down the MT3 and YAP1 genes to validate their functions. Finally, the therapeutic efficacy of combining a YAP1 inhibitor with cisplatin was confirmed by inoculating an oral cancer cell line in mice.ResultsIn our study, we analyzed 43 OSCC samples and identified 724 different genes using the weighted gene coexpression network analysis (WGCNA) method. Among these genes, MT3 stood out as strongly associated with chemotherapy resistance. Patients with high MT3 expression had worse prognoses, and MT3 levels were elevated in drug-resistant patients. Knocking down MT3 reversed tumor cell chemoresistance. We also observed that MT3 increased the expression of YAP1, potentially contributing to chemotherapy resistance by inducing tumor stemness through YAP1. In animal models, using YAP1 inhibitors improved the effectiveness of cisplatin in treating chemoresistant oral cancer.ConclusionsMT3 is related to chemotherapy resistance, which may be caused by its promotion of YAP1 expression and induction of tumor cell stemness. Inhibiting the activity of MT3 and YAP1 is helpful for increasing chemotherapy sensitivity.

Tanshinone IIA ameliorates cisplatin-induced toxicology and cisplatin resistance via regulating SLC7A11 expression.

Cisplatin, a potent chemotherapy agent, is highly effective against various cancers but is hindered by resistance and toxicities. This study aims to investigate the roles of SLC7A11, a cystine/glutamate transporter, in cisplatin resistance, and explored Tanshinone IIA as a therapeutic option. Cisplatin reduced SLC7A11 in renal cells, worsening toxicity. Cisplatin-resistant gastric cancer cells show increased SLC7A11, driving resistance, while SLC7A11 knockdown curbed resistance. Tanshinone IIA showed promise in alleviating cisplatin toxicity by enhancing SLC7A11 expression and reducing associated adverse effects, while it effectively reversed cisplatin resistance in gastric cancer cells by suppressing SLC7A11. Additionally, Tanshinone IIA counteracted cisplatin resistance by inhibiting PIAS4-mediated SUMOylation of SLC7A11. Simultaneously, overexpressing miR-375, which has been shown to target SLC7A11, exacerbated cisplatin toxicity via SLC7A11 downregulation, which Tanshinone IIA attenuates. In summary, our study unveils complex SLC7A11 regulation in cisplatin resistance and toxicity. Tanshinone IIA emerges as a promising modulator of SLC7A11 through individual pathways, offering novel insights into overcoming cisplatin resistance and reducing toxicities in cancer therapy.

Novel Platinum(IV) complexes intervene oxaliplatin resistance in colon cancer via inducing ferroptosis and apoptosis

Platinum-based chemotherapeutics are widely used for cancer treatment but are frequently limited because of dosage-dependent side effects and drug resistance. To attenuate these drawbacks, a series of novel platinum(IV) prodrugs (15a–18c) were synthesized and evaluated for anti-cancer activity. Among them, 17a demonstrated superior anti-proliferative activity compared with oxaliplatin (OXA) in the cisplatin-resistant lung cancer cell line A549/CDDP and OXA-resistant colon cancer cell line HCT-116/OXA but showed a lower cytotoxic effect toward human normal cell lines HUVEC and L02. Mechanistic investigations suggested that 17a efficiently enhanced intracellular platinum accumulation, induced DNA damage, disturbed the homeostasis of intracellular reactive oxygen molecules and mitochondrial membrane potential, and thereby activated the mitochondrion-dependent apoptosis pathway. Moreover, 17a significantly induced ferroptosis in HCT-116/OXA via triggering the accumulation of lipid peroxides, disrupting iron homeostasis, and inhibiting solute carrier family 7 member 11 and glutathione peroxidase 4 axial pathway transduction by inhibiting the expression of the phosphorylated signal transducer and activator of transcription 3 and nuclear factor erythroid 2‐related factor 2. Moreover, 17a exerted remarkable in vivo antitumor efficacy in the HCT-116/OXA xenograft models but showed attenuated toxicity. These results indicated that these novel platinum(IV) complexes provided an alternative strategy to develop novel platinum-based antineoplastic agents for cancer treatment.

Strong apoptotic response of testis tumor cells following cisplatin treatment

Most solid metastatic cancers are resistant to chemotherapy. However, metastatic testicular germ cell tumors (TGCT) are cured in over 80% of patients using cisplatin-based combination therapy. Published data suggest that TGCTs are sensitive to cisplatin due to limited DNA repair and presumably also to a propensity to undergo apoptosis. To further investigate this aspect, cisplatin-induced activation of apoptotic pathways was investigated in cisplatin-sensitive testis tumor cells (TTC) and compared to cisplatin-resistant bladder cancer cells. Apoptosis induction was investigated using flow cytometry, caspase activation and PARP-1 cleavage. Immunoblotting and RT-PCR were applied to investigate pro- and anti-apoptotic proteins. Transfections were performed to target p53- and Fas/FasL-mediated apoptotic signaling. Immunoblotting experiments revealed p53 to be induced in TTC, but not bladder cancer cells following cisplatin. Higher levels of pro-apoptotic Bax and Noxa were observed in TTC, anti-apoptotic Bcl-2 was solely expressed in bladder cancer cells. Cisplatin led to translocation of Bax to the mitochondrial membrane in TTC, resulting in cytochrome C release. Cisplatin increased the expression of FasR mRNA and FasL protein in all tumor cell lines. Targeting the apoptotic pathway via siRNA-mediated knockdown of p53 and FAS reduced death receptor-mediated apoptosis and increased cisplatin resistance in TTC, indicating the involvement of FAS-mediated apoptosis in the cisplatin TTC response. In conclusion, both the death receptor and the mitochondrial apoptotic pathway become strongly activated in TTC following cisplatin treatment, explaining, together with attenuated DNA repair, their unique sensitivity toward platinum-based anticancer drugs.