cisplatin resistance

This study focused on macrocyclic diterpenes derived from Euphorbia, particularly myrsinanes, and their potential in cytotoxic and combination treatments for resistant cancer cells. We examine premyrsinanes isolated from Euphorbia malleata and explore their cytotoxic properties.

Euphorbia malleata was collected from Taragh-Roud, Natanz, Iran. The semi-polar chloroform/acetone extract was chromatographed and fractionated using a large silica column. Fractions containing diterpene resonances were selected based on 1H-NMR spectra and were further subjected to smaller silica or Sephadex columns, followed by a recycling HPLC system. The isolated compounds were identified through 1D and 2D-NMR experiments and mass spectrometry. The cytotoxicity of the isolated compounds was assessed using the MTT assay against A2780 wild and A2780 cisplatin-resistant (R-CIS) cells, both in mono and combination treatments with cisplatin.

Using a Waters 616 HPLC pump and a YMC prep silica column, we successfully isolated two new premyrsinane diterpenes (Malleatin A and Malleatin B) alongside two known compounds (beta-sitosterol and loliolide). Malleatin A exhibited cytotoxicity against A2780 wild and A2780 R-CIS cells, with an IC50 range of 50 - 65 μM in the MTT assay. While cisplatin demonstrated significant cytotoxic effects on the A2780 wild cell line, it was ineffective against the A2780 R-CIS cells due to their resistance. However, the combination therapy of Malleatin A and cisplatin exhibited a synergistic effect, significantly increasing the mortality rate of the resistant cells compared to monotherapy. The Combination Index (CI) of 0.58 indicates effective synergy, and the Dose Reduction Index (DRI) of 3.65 suggests a favorable reduction in the dosage of cisplatin needed, potentially reducing its associated side effects.

Non-small-cell lung cancer (NSCLC) remains a deadly malignancy worldwide. Resistance to cisplatin (DDP) is a significant obstacle that limits the therapeutic efficacy in NSCLC patients.

This study investigated the role and mechanism of 24-dehydrocholesterol reductase (DHCR24) in DDP resistance in NSCLC cells.

24-dehydrocholesterol reductase levels, ferroptosis-related molecules, and proteins involved in the PI3K/AKT/GSK3β pathway were measured. The growth capacity of the cells was evaluated, and ferroptosis was assessed by measuring MDA, GSH, Fe2+, and ROS levels. The impact of DHCR24 on NSCLC DDP resistance was analyzed using a tumor xenograft assay in vivo. Ki-67 and DHCR24 expression in tumors were evaluated through immunohistochemical staining.

24-dehydrocholesterol reductase expression was elevated in DDP-resistant cells, indicating a poorer prognosis for NSCLC patients. Down-regulation of DHCR24 inhibited the growth of DDP-resistant cells and induced ferroptosis. Inhibition of DHCR24 led to the inactivation of the PI3K/AKT/GSK3β pathway and subsequent induction of ferroptosis. Inhibition of ferroptosis or activation of the PI3K/AKT/GSK3β pathway counteracted the increased DDP sensitivity induced by DHCR24 knockdown in NSCLC cells. Additionally, DHCR24 deficiency improved NSCLC DDP resistance in vivo.

24-dehydrocholesterol reductase contributes to DDP resistance in NSCLC cells by suppressing ferroptosis through the activation of the PI3K/AKT/GSK3β pathway.

Cisplatin resistance presents a considerable hurdle in the treatment of ovarian cancer, significantly impacting patient outcomes and limiting the effectiveness of chemotherapy. This study employs advanced bioinformatics techniques-including RNA sequencing (RNA-seq), DNA sequencing (DNA-seq), and chromatin immunoprecipitation sequencing (ChIP-seq)-to elucidate the molecular mechanisms underlying this resistance, with a particular focus on the long non-coding RNA (lncRNA) LINC02381. Our findings reveal that LINC02381 is significantly upregulated in ovarian cancer cells exhibiting resistance to cisplatin, suggesting its pivotal role in mediating this phenomenon. We further demonstrate that cytokines, particularly interleukin-12 (IL-12), secreted by immune cells within the tumor microenvironment, activate the Wnt signaling pathway. This activation leads to the binding of the transcription factor TCF7 to the promoter region of LINC02381, resulting in enhanced expression of this lncRNA. Notably, this interaction establishes a positive feedback loop in which LINC02381 not only promotes its own expression but also amplifies Wnt signaling activity. This cascade ultimately drives the upregulation of ATP-binding cassette (ABC) transporters, which are crucial for the efflux of cisplatin from cancer cells. Thus, the drug's intracellular concentration is reduced, and cell survival under chemotherapy pressure is facilitated. These insights uncover a novel mechanism of cisplatin resistance driven by the IL-12/Wnt/TCF7/LINC02381 axis, highlighting the complex interplay between immune signaling and drug resistance in ovarian cancer. Our findings suggest that targeting this regulatory pathway may offer promising therapeutic strategies to overcome chemotherapy resistance, paving the way for improved treatment outcomes in patients with ovarian cancer. Future research should focus on validating these mechanisms and exploring potential interventions that disrupt this feedback loop.

Tumor drug resistance is a vital obstacle to chemotherapy in lung cancer. Methionine adenosyltransferase 2A has been considered as a potential target for lung cancer treatment because targeting it can disrupt the tumorigenicity of lung tumor-initiating cells. In this study, we primarily observed the role of methionine metabolism in cisplatin-resistant lung cancer cells and the functional mechanism of MAT2A related to cisplatin resistance.

In this experimental study, we assessed the half maximal inhibitory concentration (IC50) of cisplatin in different cell lines and cell viability via Cell Counting Kit-8. Western blotting and quantitative real-time polymerase chain reaction (qRT-PCR) was used to determine the expression of relative proteins and genes. Crystal violet staining was used to investigate cell proliferation. Additionally, we explored the transcriptional changes in lung cancer cells via RNA-seq.

We found H460/DDP and PC-9 cells were more resistant to cisplatin than H460, and MAT2A was overexpressed in cisplatin-resistant cells. Interestingly, methionine deficiency enhanced the inhibitory effect of cisplatin on cell activity and the pro-apoptotic effect. Targeting MAT2A not only restrained cell viability and proliferation, but also contributed to sensitivity of H460/DDP to cisplatin. Furthermore, 4283 up-regulated and 5841 down-regulated genes were detected in H460/DDP compared with H460, and 71 signal pathways were significantly enriched. After treating H460/DDP cells with PF9366, 326 genes were up-regulated, 1093 genes were down-regulated, and 13 signaling pathways were significantly enriched. In TNF signaling pathway, CAS7 and CAS8 were decreased in H460/DDP cells, which increased by PF9366 treatment. Finally, the global histone methylation (H3K4me3, H3K9me2, H3K27me3, H3K36me3) was reduced under methionine deficiency conditions, while H3K9me2 and H3K36me3 were decreased specially via PF9366.

Methionine deficiency or MAT2A inhibition may modulate genes expression associated with apoptosis, DNA repair and TNF signaling pathways by regulating histone methylation, thus promoting the sensitivity of lung cancer cells to cisplatin.

To study the molecular mechanism of cisplatin chemotherapy resistance in colorectal cancer cells and to explore the effect of miRNA in regulating the expression of glucose transporter 3 (SLC2A3) and the proliferation and migration of colon cancer cells.

All samples were obtained from the People’s Hospital of Wuhai, Wuhai, China between June 2019 and June 2020. Real-time quantitative PCR (qRT-PCR) was carried out to check the expression of miR-103a in these cell lines. Western blotting and Luciferase reporter gene detection confirmed the regulation of the miR-103a/SLC2A3 axis. Western blotting detected the activation of SLC2A3, caspased-9 and -3.

The expression of SLC2A3 protein in colon cancer cell lines was significantly higher than that of normal colon cancer cells, while the expression of SLC2A3 miRNA showed no significant difference (P<0.05). Then, through clone formation analysis, SLC2A3 was closely related to the proliferation of human colon cancer cells. Functional recovery experiments showed that increasing the expression of miR-103a could reverse the abnormal proliferation caused by overexpression of SLC2A3.

Overall, miR-103a can inhibit the proliferation of human colon cancer cells by targeting SLC2A3, and this result will provide a potential target for the treatment of colon cancer.

Head and neck cancers are highly prevalent worldwide. Most of these lesions are diagnosed in the advanced stages of the disease. Thus, they do not often have a good long-term prognosis. Like other cancer types, head and neck cancers are managed by surgery, radiotherapy, and chemotherapy. Despite significant advances in the treatment of oral squamous cell carcinoma (OSCC), physicians encounter several challenges in the course of treatment. Various mechanisms mediate the clinical responses of a certain cancer to medications. Thus, efficient treatment planning requires adequate knowledge about the genes involved in drug resistance and the evaluation of the frequency percentage of resistance. Several studies have evaluated the causes and frequency percentages of 5-fluorouracil (5-FU) and cisplatin resistance. In this systematic review, all the relevant articles published until November 30, 2019, were retrieved from the Scopus, Embase, Medline, ISI, Web of Science, and Cochrane databases using certain MeSH and EMTTree keywords. A total of 2164 articles were retrieved of which, 18 were included in the review since they had reported the frequency percentages of drug resistance. Of all, 10 articles had evaluated cisplatin (1317 samples). A meta-analysis of the results revealed a frequency of 33% for cisplatin resistance. Eight studies had evaluated 5-FU (476 samples). A meta-analysis of the results revealed a frequency of 40.2 % for 5-FU resistance. Overcoming cisplatin resistance or 5-FU resistance can significantly enhance recovery in advanced HNSCC. Attempts should be made to eliminate the cause and use multi-drug regimens to increase the success rate of treatment.

Today, development of resistance to anticancer drugs (including cisplatin) is noticed as a major problem. Recently several studies demonstrated that palladium complexes showed remarkable cytotoxic effects against K562 cell line and could be used efficiently for treatment of many human cancers including leukemia. Hereof, K562 cells were made resistant to cisplatin using increasing concentration of cisplatin up to 4.5, and then cytotoxic effect of synthesized palladium complex was evaluated on this sub-line using MTT assay. Annexin V/PI staining using flow cytometry and scanning electron microscopy (SEM) were performed to find out the mechanism of the observed cytotoxicity. Results indicated that tested compounds had a noticeable cytotoxic effect on K562 cells 80 times more than cisplatin. Palladium complex also showed significant cytotoxicity on resistant K562 sub-line. Flow cytometry and SEM results revealed that these compounds exert their cytotoxic effect via apoptosis and it could be concluded that the novel synthesized palladium complex might be a good candidate for replacing cisplatin in case of treatment of cisplatin resistant tumors.

Fourier Transformed Infrared Spectroscopy (FTIR) has extensively been used for biological applications. Cisplatin is one the most useful antineoplastic chemotherapy drugs for a variety of different human cancers. One of the clinical problems in its application, which would consequently affect the therapeutic outcome of its application, is the occurrence of resistance to this agent. In this project three different pairs of sensitive and resistant cell lines of human ovarian A2780 and its resistant pair of A2780-CP, human ovarian OV2008 and its resistant pair of C13, and finally human lung carcinoma of HTB56 and its resistant pair of HTB56-CP were grown in the laboratory under the standard procedure. Saline was exposed to control cells, whereas 1, 5 and 10 µg/ml of cisplatin was exposed to experimental cells, for one hour. Cells were then collected and lyophilized from which spectra were taken. According to our results, we could not trigger a well-recognized cells biomolecular band at 1015 cm-1, being modified after exposure to cisplatin in all cell lines. On the other hand, there was a clear dose-dependent increase in protein β-sheet structure related peaks shift in resistant cell lines after exposure to cisplatin. This would probably indicate an easier protein interaction site for cisplatin in the resistant cell lines, which would probably inhibit cisplatin from binding to DNA, as the cytotoxic target. As a conclusion, FTIR biospectroscopy has proven its potency to identify the interactions, as well as the false engagement cellular sites for cisplatin in sensitive and resistant cell lines.

Many cancer cells show significant resistance to drugs that kill drug sensitive cancer cells and non-tumor cells and such resistance might be a consequence of the difference in metabolism. Therefore, studying the metabolism of drug resistant cancer cells and comparison with drug sensitive and normal cell lines is the objective of this research. Metabolism of cisplatin resistant and sensitive A2780 epithelial ovarian cancer cells and normal ovarian epithelium has been studied using a generic human genome-scale metabolic model and transcription data. The results demonstrate that the most different metabolisms belong to resistant and normal models, and the different reactions are involved in various metabolic pathways. However, large portion of distinct reactions are related to extracellular transport for three cell lines. Capability of metabolic models to secrete lactate was investigated to find the origin of Warburg effect. Computational results introduced SLC25A10 gene, which encodes mitochondrial dicarboxylate transporter involved in exchanging of small metabolites across the mitochondrial membrane that may play key role in high growing capacity of sensitive and resistant cancer cells. The metabolic models were also used to find single and combinatorial targets that reduce the cancer cells growth. Effect of proposed target genes on growth and oxidative phosphorylation of normal cells were determined to estimate drug side-effects. The deletion results showed that although the cisplatin did not cause resistant cancer cells death, but it shifts the cancer cells to a more vulnerable metabolism