Cisplatin-resistant Cancer Cells Research Articles

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.

Dasatinib induces apoptosis and autophagy by suppressing the PI3K/Akt/mTOR pathway in bladder cancer cells.

Bladder cancer is a common genitourinary malignant disease worldwide. Dasatinib is a small molecule inhibitor of Src family kinases. We investigated the anticancer effect and putative molecular mechanisms of dasatinib on T24 and cisplatin-resistant T24R2 human bladder cancer cells. Cell proliferation was measured using Cell Counting Kit-8 (CCK-8) and colony formation in dasatinib treated bladder cancer cells. Flow cytometry was used to determined cell cycle arrest and apoptosis. The expression of apoptosis and autophagy related proteins were detected by western blot analysis. In bladder cancer cells, dasatinib significantly reduced cell proliferation, colony formation, and induced G1-phase arrest. Dasatinib triggered apoptosis along with an increased expression of apoptosis-related genes (caspases, PARP, and cytochrome c). Down-regulation of Bcl-2 and up-regulation of Bad, which are hallmarks of apoptosis, were found to play a dominant role in mediating the effects of dasatinib treatment. We further showed that dasatinib inhibits p-Src, p-PI3K, p-Akt, and p-mTOR in bladder cancer cells. Dasatinib also increased the expression of markers of autophagy flux such as LC3-II and p62. These results confirmed that dasatinib is a potent chemotherapeutic drug which induces apoptosis and autophagy by suppressing the PI3K/Akt/mTOR pathway in bladder cancer cells.

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.

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.

M6A epitranscriptome analysis reveals differentially methylated transcripts that drive early chemoresistance in bladder cancer.

N 6-Methyladenosine (m6A) RNA modifications dynamically regulate messenger RNA processing, differentiationand cell fate. Given these functions, we hypothesized that m6A modifications play a role in the transition to chemoresistance. To test this, we took an agnostic discovery approach anchored directly to chemoresistance rather than to any particular m6A effector protein. Specifically, we used methyl-RNA immunoprecipitation followed by sequencing (MeRIP-seq) in parallel with RNA sequencing to identify gene transcripts that were both differentially methylated and differentially expressed between cisplatin-sensitive and cisplatin-resistant bladder cancer (BC) cells. We filtered and prioritized these genes using clinical and functional database tools, andthen validated several of the top candidates via targeted quantitative polymerase chain reaction (qPCR) and MeRIP-PCR. In cisplatin-resistant cells, SLC7A11transcripts had decreased methylation associated with decreased m6A reader YTHDF3 binding, prolonged RNA stability, and increased RNA and protein levels, leading to reduced ferroptosis and increased survival. Consistent with this, cisplatin-sensitive BC cell lines and patient-derived organoids exposed to cisplatin for as little as 48 h exhibited similar mechanisms of SLC7A11 upregulation and chemoresistance, trends that were also reflected in public cancer survival databases. Collectively, these findings highlight epitranscriptomic plasticity as a mechanism of rapid chemoresistance and a potential therapeutic target.

Overcoming Cancer Resistance to Platinum Drugs by Inhibiting Cholesterol Metabolism.

Drug resistance is a serious challenge for platinum anticancer drugs. Platinum complexes may get over the drug resistance via a distinct mechanism of action. Cholesterol is a key factor contributing to the drug resistance. Inhibiting cellular cholesterol synthesis and uptake provides an alternative strategy for cancer treatment. Platinum(IV) complexes FP and DFP with fenofibric acid as axial ligand(s) were designed to combat the drug resistance through regulating cholesterol metabolism besides damaging DNA. In addition to producing reactive oxygen species and active platinum(II) species to damage DNA, FP and DFP inhibited cellular cholesterol accumulation, promoted cholesterol efflux, upregulated peroxisome proliferator-activated receptor alpha (PPARα), induced caspase-1 activation and gasdermin D (GSDMD) cleavage, thus leading to both apoptosis and pyroptosis in cancer cells. The reduction of cholesterol significantly relieved the drug resistance of cancer cells. The double-acting mechanism gave the complexes strong anticancer activity in vitro and in vivo, particularly against cisplatin-resistant cancer cells.

Two Enhances the Cisplatin Sensitivity of Cervical Cancer Cells via Suppression of c-MET Expression.

The drug resistance of chemotherapeutic agents leads to unsatisfactory survival rates for cervical cancer (CC) patients. We aimed to explore the effect of FOXP2 on the sensitivity of CC cells to cisplatin (DDP) and its mechanism in Changde, China in 2018. A Total of 6 cervical cancer tissue samples including 3 patients with cisplatin sensitivity and 3 patients with cisplatin resistance, who received DDP-based treatment, were obtained from Changde First People's Hospital, Changde City during 2021, and FOXP2 level was detected by Western blot. The expression levels of FOXP2 and c-MET (hepatocyte growth factor receptor, c-MET) in cells were determined by q-PCR and Western blot analysis. The cell survival, apoptosis, and clone formation were analyzed by flow cytometry, MTT assay, or clone formation assay. Dual-luciferase reporter assays and Chromatin immunoprecipitation were applied to verify the regulation between FOXP2 and c-MET. FOXP2 was downregulated in cisplatin-resistant cervical cancer tissues and cells compared with control. FOXP2 overexpression in SiHa/DDP cells inhibited cell proliferation and promoted cell apoptosis, whereas down-regulation of FOXP2 in SiHa cells had the opposite result. FOXP2 enhanced chemosensitive to DDP in CC cells. FOXP2 is negatively correlated with c-MET expression level in SiHa and SiHa/DDP cells. Mechanistically, FOXP2 binds to the promoter region of c-MET to regulate its expression in CC cells negatively. Overexpression of c-MET can attenuate the enhancement of DDP-induced apoptosis caused by FOXP2 overexpression. This is a novel study on the role of FOXP2 in promoting the DDP sensitivity of CC cells by inhibiting c-MET. The FOXP2/c-MET signaling axis uncovered in the present study may be a novel therapeutic target for the DDP therapy resistance of CC.