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. 2025 Nov 26;14(11):7521–7535. doi: 10.21037/tcr-2025-1526

A novel pyridazinone and thiophene compound IMB5043 activated apoptosis and autophagy in cisplatin-resistant non-small cell lung cancer cells

Yingzheng Hou 1, Xueting Cao 1, Rui Cao 1, Hongmei Tang 1, Jing Chen 1,✉
PMCID: PMC12686209  PMID: 41378041

Abstract

Background

Lung cancer is still one of the top three malignant tumors in the world at present and one of the cancers with the lowest survival rate. Cisplatin is one of the most commonly used chemotherapy drugs, but the development of drug resistance can lead to the death of patients who are ineffective to the treatment. IMB5043 is a pyridazinone and thiophene compound which is cytotoxic to cancer cells. This article aims to explore its effect on cisplatin-resistant lung cancer cells.

Methods

Methylthiazolyldiphenyl-tetrazolium bromide (MTT) assay was used to detect the cyto-toxicity of different concentrations of cisplatin and IMB5043 on non-small cell lung cancer (NSCLC) H460 cells and its cisplatin-resistant cell (H460/DDP). The effect of IMB5043 on cell migration and invasion and its molecular mechanism were studied by scratch experiment, transwell experiment and Western blot. Hoechst 33342 staining, acridine orange/ethidium bromide (AO/EB) double fluorescence staining and Western blot were used to detect whether IMB5043 induced cell apoptosis and explore its molecular mechanism. Acridine orange (AO) staining and Western blotting were used to detect whether IMB5043 induced autophagy in cells.

Results

IMB5043 induced the death of cisplatin-resistant NSCLC cells by activating apoptosis and autophagy, and inhibited the epithelial-mesenchymal transition (EMT) pathway to reduce cell migration and invasion.

Conclusions

IMB5043 is an effective pyridazinone and thiophene derivatives with antitumor effects and may be suitable for cisplatin-based combination therapy in a subset of patients with cisplatin-resistant NSCLC.

Keywords: IMB5043, cisplatin-resistant, apoptosis, autophagy, lung cancer

Highlight box.

Key findings

• Our research may provide a new idea for the development of new cisplatin resistant drugs for lung cancer.

What is known and what is new?

• IMB5043 has been shown to induce cell death in liver cancer cells by triggering DNA damage and activating the ataxia telangiectasia mutated- checkpoint kinase 2-p53 (ATM-CHK2-p53) pathway. Another structurally similar compound, IMB5036, overcame multidrug resistance in breast cancer cells by inducing pyroptosis.

• This study demonstrated that IMB5043 reversed cisplatin's cytotoxic effects in cisplatin-resistant non-small cell lung cancer cells. It suppressed migration and invasion through the epithelial-mesenchymal transition pathway, while also inducing apoptosis and autophagy.

What is the implication, and what should change now?

• These findings provide a basis for further study of the role of IMB5043 in lung cancer and other malignant tumors and for clinical research on this topic.

Introduction

Background

Lung cancer is one of the most common and deadliest cancers worldwide. Approximately 80–85% of cases are classified as non-small cell lung cancer (NSCLC), while small cell lung cancer (SCLC) accounts for 10–15% (1,2). Common treatments for NSCLC include surgical resection as well as radiotherapy and chemotherapy. Surgical resection is suitable for early-stage NSCLC patients, while radiotherapy and chemotherapy are treatment options for locally advanced unresectable lung cancer patients (3). Cisplatin is a very strong non-specific cell cycle blocker that is always used as a chemotherapeutic agent to treat various cancers, including NSCLC (4). However, this treatment requires the generation of a multi-pronged adaptive response in malignant cells, which makes them less susceptible to the anti-proliferative and cytotoxic effects of drugs, leading to a recovery of proliferation (5). These mechanisms enable cancer cells to survive and grow within the human body, leading to drug resistance against treatment (6). This drug resistance is an important cause of treatment failure in NSCLC, leading to tumor recurrence and disease progression (7,8). The molecular action mechanism of cisplatin resistance is relatively complex, which mainly includes abnormalities of DNA damage repair function (9,10), intracellular drug inactivation (11), autophagy (12), affecting both internal and external apoptotic pathways (13), changes of drug resistance-related genes (14), etc. In order to better understand and overcome drug resistance to existing therapies, it is necessary to study new drugs and their molecular mechanisms involved in the development of NSCLC.

2-(4,5-dibromo-6-oxo-1,6-dihydropyridazin-1-yl)-N-methyl-N-[(thiophen-3-yl) methyl] acetamide, named as IMB5043 (Figure 1), is a new compound of pyridazinone and thiophene, which has been newly discovered in recent years. It has been preliminarily proved to induced liver cancer cell death by activating the DNA damage response, further activating the ATM-CHK2-p53 axis (15). Pyridazine is a heterocyclic compound containing nitrogen atoms, which has a different structure from other heterocyclic compounds also has biological activity that can be widely used (16). Pyridazinone compounds have attracted great attention in the field of biological development research due to their good biological therapeutic effects (17). However, it is still unknown whether IMB5043 can induce death in cisplatin-resistant NSCLC cells.

Figure 1.

Figure 1

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Structure of IMB5043.

In the present study, we found that IMB5043 inhibited cell growth and proliferation by activating apoptosis and autophagy in H460/DDP cells. Besides, IMB5043 inhibited cell migration and invasion by epithelial-mesenchymal transition (EMT). The IMB5043 effects were more prominent in cisplatin-resistant cell lines. Our research may provide a new idea for the development of new cisplatin resistant drugs for lung cancer. We present this article in accordance with the MDAR reporting checklist (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-1526/rc).

Methods

Potential target identification based on Pharmmapper

PharmMapper [PharmMapper (lilab-ecust.cn)] is an online tool that identifies potential drug targets by matching queried compounds to the internal pharmacophore model database for reverse pharmacophore matching. Downloaded the SDF format of IMB5043 from PubChem Compound {2-(4,5-Dibromo-6-oxo-1,6-dihydropyridazin-1-yl)-n-methyl-n-[(thiophen-3-yl)methyl]acetamide|C12H11Br2N3O2S|CID 31203659 - PubChem (nih.gov)} and uploaded it to PharmMapper. After a series of parameters were set, target recognition analysis was performed to obtain the relevant data information of the first 300 potential protein targets.

Bioinformatics and network pharmacology analysis

We inputted the top 300 potential targets, selected Homo sapiens, and then carried out Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis (18-20). The information associated with the first 100 potential pathways was acquired. Hypergeometric analysis was used for testing significance threshold with a P<0.05. For FDR value <0.05, we selected the Top 20 pathway, and mapped senior bubbles by the R 4.2.1.

Cell culture

IMB5043, human lung cancer H460 cell lines and cisplatin-resistant human lung cancer H460/DDP cell lines received as donation from the Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College (Beijing, China). Cells were cultured in RPMI 1640 medium supplemented with 10% fetal bovine serum (FBS), 1% penicillin-streptomycin at a humidified atmosphere (37 ℃, 5% CO2).

MTT assay

The drug resistance index of H460/DDP cells and the toxic effect of IMB5043 on cells were detected by MTT assay. Cells were seeded into a 96-well plate with 3,000 cells per well, cultivated overnight, and incubated with a series of concentrations of cisplatin (0–187.5 µM) or IMB5043 (0–10 µM) or cisplatin and IMB5043 (3µM) combined application. At the end of the intervention period, removed the cell medium, and added 20 µL of 5 mg/mL MTT to each well. After incubating for 4 h at 37 ℃ in the dark, 150 µL of DMSO was added, and the absorbance was measured at 570 nm with a microplate reader. The cell viability rate was calculated by: (A treated−A blank)/(A control−A blank) ×100%. At the same time, worked out the semi-inhibitory concentration (IC50) of cisplatin or IMB5043 or cisplatin and IMB5043 (3 µM) combined application, and then the drug resistance index of H460/DDP cells was calculated (drug resistance index = IC50 of H460/DDP cells/IC50 of H460 cells).

Wound healing assay

H460 and H460/DDP cells were plated into 6-well plates (5.5×105/mL), and when the cell density reaches 90%, vertically scraped the cells with a 100 µL-pipette tip. The scraped cells were washed off with PBS. Added 2 mL serum-free medium containing different concentrations of IMB5043 (0, 2, 4 and 8 µM) into each well and photographed the migrated cells under a light microscope at different duration (0 and 48 h).

Transwell assay

Transwell migration and invasion assays (Corning Life Science, USA) were performed on 24-well plates with polycarbonate membrane inserts (8 µm pore size). H460 and H460/DDP cells were seeded in 200 µL serum-free medium with different concentrations of IMB5043 (0, 2, 4 and 8 µM) and placed in the upper chamber. The lower chambers were supplemented with RPMI1640 and 10% FBS. To assess cell invasion, total 100 µL matrigel was dispersed on the upper side of the transwell cell migration chamber. After incubation for 24 h, the migratory or invasive cells were fixed and stained with 0.1% crystal violet. The number of cells at the bottom of the membrane were quantified under a light microscope in three predetermined fields at a magnification of 200.

Hoechst 33342

H460 and H460/DDP cells were seeded in 6-well plates at a density of 3×105 cells/well. After culturing overnight, it was changed to serum-free medium with different concentrations of IMB5043 (0, 2, 4 and 8 µM) and cultured for 48 h. The medium was aspirated and each well washed twice with PBS. Then 1 mL of Hoechst 33342 (0.5 µg/mL) was added to each well. After incubation at 3 ℃ for 30 min, PBS was used to wash the excess Hoechst 33342. Changes in the cell nucleus were photographed with fluorescence microscopy (OLYMPUS-BX53, magnifying power of 200×).

Acridine orange/ethidium bromide (AO/EB) fluorescent staining

Cells were seeded in 6-well plates at a density of 3×105 cells/well. After culturing overnight, added different concentrations of IMB5043 (0, 2, 4 and 8 µM) and cultured for 48 h. Then, cleaning cells with PBS. According to the ratio of AO: EB =1:1, the working solution was mixed. After incubation at room temperature for 5 min, the cell morphology was observed under fluorescence microscope (OLYMPUS-BX53, magnifying power of 200×).

Acridine orange (AO) fluorescent staining

Cells were seeded in 6-well plates at a density of 3×105 cells/well. After culturing overnight, added different concentrations of IMB5043 (0, 2, 4 and 8 µM) and cultured for 48 h. Sucked out the culture medium, and washed each well twice with PBS. Then 1 mL of AO (1 µg/mL) was added to each well. After incubation at room temperature for 30 min, PBS was used to wash the excess AO. The cell morphology was observed under fluorescence microscope (OLYMPUS-BX53, magnifying power of 200×).

Western blot

H460 and H460/DDP cells were seeded into 6-wells (5.5×105/mL) and cultured for 24 h. Then, added 2 mL culture medium containing different concentrations of IMB5043 (0, 2 and 4 µM) into each well for 48 h. Cells were split in radio-immunoprecipitation assay (RIPA) lysis buffer (Beyotime). A standard bicinchoninic acid (BCA) assay was used to measure protein concentration. The quantity was determined to 1 µg/µL. Equal amounts of protein (15 µg) were resolved on 6–12% SDS-PAGE and transferred onto polyvinylidenedifluoride (PVDF) membranes. Membranes were blocked for 2 h in 5% skim milk and then incubated with primary antibodies (E-cadherin, Slug, Snail, Bax, Bcl-2, p53, cytochrome C, cleaved-caspase 3, cleaved-PARP, cleaved caspase-9, caspase8, p62, LC3 and β-actin) overnight at 4 ℃. After incubation with HRP-conjugated secondary anti-bodies, the membranes were intuitionistic using the enhanced chemiluminescence system of SH-Compact 523 (Shenhua Science Technology Co., Ltd., Hangzhou, China). β-actin was used as a loading control. The protein expression was evaluated using Image J software (NIH, Bethesda, USA).

Statistical analysis

All experiments were repeated three times, and the experimental results were expressed as mean values ± standard. Data were analyzed using GraphPad Prism 8 (GraphPad Software, San Diego, CA, USA) and Image J. Statistical significance was determined using two-tailed unpaired Student’s t-test and Dunnett test, and P values <0.05 were considered to indicate significant differences.

Results

Potential target proteins of IMB5043 and the bioinformatics and network pharmacology analysis

We obtained the related information of the first 300 potential protein targets by PharmMapper (Table S1). Bubble plots were then plotted with R 4.2.1 by GO and KEGG enrichment analysis. IMB5043 may affect the negative regulation of protein hydrolysis and apoptosis. Cell components may be destroyed by IMB5043 through cytosol, cytoplasm and other parts. IMB5043 may participate in molecular functions such as identification of protein binding and ATP binding. Pathway enrichment analysis revealed that IMB5043 was involved in pathways in cancer, apoptosis and autophagy (not displayed). It also might be involved in platinum-based resistance of NSCLC (Figure 2). Therefore, NSCLC H460 cells and NSCLC cisplatin-resistant H460/DDP cells were selected for subsequent studies.

Figure 2.

Figure 2

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GO and KEGG analyses. (A) The top 20 signaling pathways of IMB5043 in GO-BP analysis; (B) the top 20 signaling pathways of IMB5043 in GO-CC analysis; (C) the top 20 signaling pathways of IMB5043 in GO-MF analysis; (D) the top 20 signaling pathways of IMB5043 in KEGG pathways analysis. BP, biological process; CC, cellular component; GO, Gene Ontology; KEGG, Kyoto Encyclopedia of Genes and Genomes; MF, molecular function.

Cisplatin induced cell death in NSCLC cell lines

In order to determine the drug resistance index of H460/DDP cells to cisplatin, both the cell lines have been treated with different concentrations of cisplatin (0, 1.46, 2.93, 5.86, 11.72, 23.44, 46.875, 93.75 and 187.5 µM) for 48 h. As expected, H460 cells showed stronger cisplatin sensitivity compared with H460/DDP cells (Figure 3A). The IC50 of cisplatin to H460 cells and H460/DDP cells were 9.96±0.38 and 43.74±1.54 µM, respectively (P<0.05). The drug resistance index of H460/DDP cells was 4.39.

Figure 3.

Figure 3

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Proliferative inhibitory effect of DDP and IMB5043 on NSCLC cells. (A) H460 and H460/DDP cells were treated with indicated DDP concentrations for 48 h. (B) H460 and H460/DDP cells were treated with indicated IMB5043 concentrations or with control (0 µM) for 48 h. (C) H460 and H460/DDP cells were treated with IMB5043 (3 µM) and indicated DDP concentrations for 48 h. *, compared with control, P<0.05; #, compared with H460 cells, P<0.05. All data are shown as the mean ± standard deviation of three in-dependent experiments. DDP, cisplatin; NSCLC, non-small cell lung cancer.

IMB5043 suppressed proliferation of H460 and H460/DDP cells

MTT assay was used to examine the anti-proliferative of IMB5043 at different concentrations (0, 0.15625, 0.3125, 0.625, 1.25, 2.5, 5 and 10 µM) on H460 and H460/DDP cells after treatment for 48 h. Results showed that the IC50 value was 4.38±0.04 µM for H460 cells and 3.01±0.06 µM for H460/DDP cells (P<0.01). The results indicated that IMB5043 inhibited the viability of H460/DDP cells more obviously compared with H460 cells. The significant inhibitory effect of IMB5043 on cells began with 0.16 µM, and with the increase of concentration, the inhibitory effect gradually increased (Figure 3B).

IMB5043 and cisplatin coordinately suppressed proliferation of H460 and H460/DDP cells

Our next step was to investigate whether IMB5043 combined with cisplatin can inhibit cell proliferation, especially in H460/DDP cell lines. Thus, we treated two cell lines with IMB5043 (3 µM) indicated concentrations of cisplatin (0, 1.46, 2.93, 5.86, 11.72, 23.44, 46.875, 93.75 and 187.5 µM) for 48 h, to validate the resistance of H460/DDP cells. As expected, the IC50 of cisplatin to H460 cells and H460/DDP cells were reduced to 5.83±0.42 and 8.93±0.26 µM, respectively (P<0.05). Compared with H460 cells, H460/DDP cell lines showed highly decreased viability. Our data unambiguously indicate cisplatin in combination with IMB5043 reduced the sensitivity of H460/DDP cells to cisplatin (Figure 3C).

IMB5043 suppressed the wound healing, migration and invasion of H460 and H460/DDP cells through EMT

In order to explore how IMB5043 affects the motility of cells, we conducted wound healing assays with H460 and H460/DDP cells. After treatment with IMB5043 for 48 h, the open wound area was measured at 0 and 48 h (Figure 4). The results showed that, compared with 0h, the wound area of the two cells decreased in different degrees after 48 h, and the wound area of the control group decreased the most, indicating that IMB5043 could inhibit the migration of the two kinds of cells in a concentration-dependent manner (P<0.05). In addition, both H460 and H460/DDP have clear wound boundaries, and H460/DDP cells wounds healed more slowly, indicating that the inhibitory effect of H460/DDP cells is more obvious (P<0.05). Overall, the cell mobility decreased with the increase of IMB5043 concentration.

Figure 4.

Figure 4

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IMB5043 suppressed the wound healing, migration and invasion of H460 and H460/DDP cells. (A,B) Cells were treated with 2, 4 and 8 μM IMB5043 or with control (0 μM) for 48 h. Wound healing assay was performed and the cell migration rate was measured after 0 and 48 h upon treatment. Representative images are shown. Three independent experiments were used for statistical evaluation. (C-E) Representative images of transwell assays. Cells were treated with 2, 4 and 8 μM IMB5043 or with control (0 μM) for 48 h. Cells stained with 0.1% crystal violet; magnifying power of 200×. *, compared with control, P<0.05; #, compared with H460 cells, P<0.05. All data are shown as the mean ± standard deviation of three in-dependent experiments. DDP, cisplatin.

To further study the influence of IMB5043 on migration and invasion, we carried out transwell assays. As shown in Figure 4, in the control group, there was no significant difference in the number of H460 and H460/DDP migrating cells, but with the increase of IMB5043 concentration, the number of H460/DDP migrating cells was less than that of H460 cells (P<0.05). In the invasion experiment, with the increase of IMB5043 con-centration, the number of invasive cells in the two cells decreased obviously. These results showed that H460/DDP cells were more sensitive to IMB5043 than H460 cells.

Epithelial-mesenchymal transition (EMT) is closely related to migration and invasion by degrading and remodeling extracellular matrix (21). E-cadherin is a major regulator in EMT. To investigate the molecular mechanisms behind the phenotypical effects of IMB5043 on H460 and H460/DDP cells, we checked the expression of E-cadherin by Western blot. The result showed that IMB5043 obviously upregulated the E-cadherin protein level in concentration dependent manner. Slug and Snail are well-known transcription factors which mediated EMT (21). Therefore, we checked the expression of Slug and Snail by Western blot in H460 and H460/DDP cells. IMB5043 inhibited expression of Slug and Snail in a dose-dependent manner (Figure 5). The expression level of H40/DDP cells was higher than H460 cells for E-cadherin, Slug and Snail proteins, indicating that H460/DDP cells were more sensitive to IMB5043 than H460 cells. Taken together, IMB5043 inhibited the motility of cells through upregulating E-cadherin and downregulating Slug and Snail.

Figure 5.

Figure 5

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IMB5043-induced inhibition of EMT in NSCLC cell lines. (A) The changes of E-cadherin, Slug and Snail protein expression were detected by Western blot; (B-D) histograms depicting the relative gray value of the related proteins measured using ImageJ. All data are shown as the mean ± standard deviation of three independent experiments. *, compared with control, P<0.05; #, compared with H460 cells, P<0.05. DDP, cisplatin; EMT, epithelial-mesenchymal transition; NSCLC, non-small cell lung cancer.

IMB5043 induced apoptosis in H460/DDP cells

Further, we wanted to explore the molecular mechanism of IMB5043-induced cell death. After treatment with different concentration IMB5043 for 48 h, Hoechst 33342 was performed to observe the nuclear changes. As shown in Figure 6A,6B, with the increase of IMB5043 concentration, the number of apoptotic cells gradually increased. The result showed that IMB5043 could induce cell apoptosis. This data was also in context with AO/EB staining showing apoptotic cells. AO/EB staining result showed that IMB5043 increased the number of apoptotic cells of H460/DDP cells in a concentration-dependent manner, while H460 cells had few apoptotic cells (Figure 6C,6D). Western blotting analysis demonstrated that IMB5043 increased the expression levels of Bax, p53, cytochrome C, cleaved-caspase 3, cleaved-PARP, caspase8 and cleaved caspase-9, but decreased the expression levels of Bcl-2 and Survivin in H460/DDP cells (Figure 6E-6G), the ratio of Bax/Bcl-2 increased. The changes of these proteins indicated that intrinsic and extrinsic apoptotic pathways are involved in IMB5043-induced cell death. While in H460 cells, the expression of Bax decreased, the expression of Bcl-2 increased and the ratio of Bax/Bcl-2 decreased. At the same time, the expression levels of p53, cytochrome C, Survivin, cleaved-PARP and cleaved caspase-9 were decreased. The expression level of Caspase8 was not changed. These changes were contrary to H460/DDP cells, indicating that IMB5043 did not activate apoptosis through intrinsic and extrinsic apoptotic pathways in H460 cells. These results indicated IMB5043-based activation of apoptosis in H460/DDP cells.

Figure 6.

Figure 6

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IMB5043 induced apoptosis in H460/DDP cells. (A-D) Upon staining with Hoechst 33342 or AO/EB, cells were observed by fluorescence microscopy. Representative photos are shown. Scale bar =200 µm; (E-G) the changes of Bax, Bcl-2, Cleaved-caspase 3, CleavedPARP, Cleaved caspase-9, Cytochrome C, p53 and Caspase8 protein expression were detected by Western blot. Used ImageJ to measure the histogram of relative gray values of the relevant protein. All data are shown as the mean ± standard deviation of three independent experiments. The arrows to an apoptotic cell nucleus. *, compared with control (0 μM), P<0.05. AO/EB, acridine orange/ethidium bromide; DDP, cisplatin.

IMB5043 induced autophagy in H460/DDP cells

In order to further study the mechanism of IMB5043 causing H460 cell death, AO staining was carried out. Our data showed that both in H460 and H460/DDP cells, IMB5043 treatment activated autophagy (Figure 7A,7B). Then, we analyzed the activation of autophagy by Western blot for the conversion of light chain 3 (LC3-I) to LC3-II protein and p62. P62 as an autophagic receptor, it binds to LC3 and targets autophagy to clear cancer cells (22). As showed in Figure 7C-7E, both in H460 and H460/DDP cells, LC3-II protein expression was increased and p62 was decreased, indicating that autophagy was activated. Therefore, our data show that IMB5043 activates apoptosis and autophagy in H460/DDP cells, while it activates autophagy in H460 cells.

Figure 7.

Figure 7

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IMB5043 induced autophagy in H460 and H460/DDP cells. (A,B) Cells were treated with control, IMB5043 (2, 4 and 8 µM) for 48 h. Upon staining with acridine orange (1 µg/mL), cells were observed by fluorescence microscopy. Representative photos are shown. Scale bar =113 µm; (C-E) upon treatment with 0, 2, 4 µM IMB5043, autophagy marker LC3-I/II and p62 were detected. Representative blots are shown. Histograms depicting the relative gray value of the related proteins measured using ImageJ. All data are shown as the mean ± standard deviation. *, compared with control (0 µM), P<0.05. DDP, cisplatin.

Discussion

Platinum-based chemotherapy drugs such as cisplatin and carboplatin are often used to treat a variety of solid tumors, including lung cancer. However, the emergence and development of resistance is a complex process. Therefore, more studies are needed to study the molecular mechanisms of drug resistance, focusing on new drugs or drugs that can be used in combination with platinum-based therapy (23). In this study, we focused on the effect and molecular mechanism of IMB5043 on cisplatin-resistant and sensitive NSCLC cells.

The IMB5043 molecule contains two major parts, the pyridazinone and the thiophene moieties (15). Pyridazinone compounds are one kind of pyridazine compounds, which have been reported to have extensive pharmacological activities (24) and can inhibit the proliferation and migration of many tumors, such as osteosarcoma (25), colon cancer and breast cancer (26). When c-Met tyrosine kinase is over-expressed, it will cause tumor occurrence and promote its metastasis, and cause therapeutic resistance (27). Pyridazinone derivatives, as inhibitors of c-Met tyrosine kinase, showed significant anti-tumor activity on c-Met driven EBC-1 tumor xenografts (28). Thiophene and its derivatives have shown good anti-tumor activity in recent years (29). Studies have found that thiophene compounds can inhibit the proliferation of lung cancer and breast cancer cells (30-32), and affect the growth of colon cancer cells through apoptosis (33). Our data showed that IMB5043 or combined application with cisplatin can inhibit the proliferation of lung cancer cells, especially in cisplatin-resistant lung cancer cells.

EMT is an initial step in the complex process of tumor metastasis (34,35). When EMT occurs, the expression of N-cadherin in cells is increased while that of E-cadherin is decreased (36,37). This process is regulated by EMT transcription factors, such as the SNAIL family zinc finger transcription factors (Snail and Slug) (38). The Snail family includes three members: Snail1 (Snail), Snail2 (Slug), and Snail3 (Smuc) (39). Research has found that E-cadherin is a direct target gene of Snail, which mainly binds to the E-box sequence on the E-cadherin promoter through its zinc finger region, achieving the effect of suppressing E-cadherin transcription (40). Previous studies have shown that IMB5043 can induce DNA damage in liver cancer cells and upregulate the expression of p53. P53 has been found to be related to the metastasis of NSCLC (15,41). Therefore, we speculated that IMB5043 may downregulate the expression of snail and slug through the p53 signaling pathway, promoting the expression of E-cadherin, thus inhibiting the migration and invasion of NSCLC cells. However, further experimental validation is needed.

Apoptosis and autophagy are the basic control mechanisms of eukaryotic cells and an important way of tumor cell death (42). Theoretically, both apoptosis and autophagy can inhibit tumor growth. Apoptosis prevents tumor cells from growing, while autophagy can eliminate tumor cells. However, with the development of cancer, autophagy can eliminate tumor on the one hand, and improve the survival rate of tumor cells under emergency conditions such as hypoxia, which leads to chemotherapy resistance (43). IMB5036 is similar to IMB5043 in structure and has been found to inhibit the growth of pancreatic cancer and liver cancer cells by activating apoptosis (44,45). In addition, pyridazinone compounds damaged proteasome activity by accumulating ROS, and induced the occurrence of internal apoptosis pathway, thus causing leukemia, breast and lung cancer cells death (46). Thiophene derivatives, as a new tubulin interacting agent, activated caspase-3 in neuroblastoma in a time-dependent manner, and finally induced apoptosis (47). Zhao et al. successfully synthesized several dehydroabietylamine derivatives containing heterocyclic ring, such as thiophene and pyrazine ring. It was found that they can inhibit the proliferation of liver cancer, lung cancer, breast cancer and cervical cancer cells and induce apoptosis of liver cancer cells (48). Although these findings showed that pyridazinone or thiophene derivatives can induce the death of lung cancer cells through apoptosis, our study found that IMB5043 did not induce the death of H460 cells through apoptosis. On the contrary, in H460/DDP cells, IMB5043 had stronger cytotoxicity and induced cell death by activating intrinsic and extrinsic apoptotic pathways. In our opinion, the particular strength of this study is the usage of a new compound containing pyridazinone and thiophene, which may also be the reason for the difference from the known research results.

When cells are under stress or toxic damage, the permeability of the mitochondrial outer membrane increases, leading to the release of cytochrome C. Cytosolic cytochrome C forms an apoptosome with apoptotic protease activating factor-1 (APAF-1) and caspase-9, catalyzing the cleavage of pro-caspase-9 into active caspase-9. The activated caspase-9 then activates caspase-3, thereby initiating intrinsic apoptosis (49-51). In our study, the expression of cytoplasmic cytochrome C in H460/DDP cells increased after IMB5043 treatment, IMB5043 downregulated the anti-apoptotic protein Bcl-2, upregulated the pro-apoptotic protein Bax, and simultaneously increased the expression of caspase-9 and caspase-3, activating the intrinsic apoptotic pathway. When extracellular death ligands, such as tumor necrosis factor (TNF) or Fas ligand (FasL), bind to specific death receptors on the cell surface, caspase-8 is activated, initiating the extrinsic apoptotic pathway (52). After treatment with IMB5043, the expression of caspase-8 in H460/DDP cells increased, suggesting that IMB5043 can also activate the extrinsic apoptotic pathway. It is worth noting that the intrinsic and extrinsic pathways are interrelated and can mutually regulate each other, thereby amplifying the signals of cell apoptosis (52).

P53 is one of the genes associated with sensitivity to cancer chemotherapy. Compared to the cisplatin-resistant H460/DDP cells, H460 cells express the wild-type p53. Wang et al. research indicated that the expression of p53 protein in H460/DDP cells is in the cytoplasm, and the phosphorylation function of the protein was lost. Gene sequencing results showed that there was an insertion mutation of ‘T’ after the 277th nucleotide of the p53 gene DNA sequence in the resistant strain, resulting in a loss of 39 amino acids at the N-terminus of the protein compared to the wild-type P53 protein, which weakens the apoptosis induced by DDP and leads to the occurrence of resistance (53). Our research results showed that IMB5043 enhanced the sensitivity of H460/DDP cells to cisplatin, and it specifically increased p53 protein expression only in H460/DDP cells. IMB5043 may reverse the cisplatin resistance in H460/DDP cells through p53. In addition, p53, as a transcription factor, can inhibit the expression of Bcl-2 either directly or indirectly and promote the expression of TNF receptor-associated apoptosis-inducing ligand (TRAIL) and death receptor 5 (DR5), thereby activating intrinsic and extrinsic apoptosis (49,54,55).

An increasing number of studies have shown that p53 not only regulates apoptosis but also participates in autophagy. Gupta et al. developed a Boolean model of a G1/S checkpoint regulatory network, which described how miR-16 enhances the ataxia telangiectasia mutated (ATM)/p53 pathway in tumor cells during G1/S checkpoint-induced DNA damage by targeting protein wild-type p53-induced phosphatase1 (Wip1). Once p53 was activated, it can induce autophagy and apoptosis through the DNA damage-regulated autophagy modulator 1 (DRAM1) and Bax pathway (56). Some studies have shown that DRAM1 is necessary for p53 to promote autophagy and is also essential for p53-mediated apoptosis. This suggests that p53-mediated autophagy through DRAM1 may contribute to the tumor-suppressive function of p53 (57). IMB5043 induced apoptosis and autophagy in H460/DDP cells possibly through the regulation of p53, and this autophagy was cytotoxic, working in conjunction with apoptosis to induce cell death. However, the mechanism of IMB5043-induced autophagy in H460 cells still requires further investigation. We have not validated studies from other perspectives, such as whether apoptosis or autophagy inhibitors will save IMB5043-induced cell death, and there remains a lack of study of other cell death pathways, which may also contribute to cell death induced by IMB5043.

Conclusions

Our study showed that IMB5043 combined with cisplatin can improve the sensitivity of H460/DDP cells to cisplatin. IMB5043 inhibited the migration and invasion of cisplatin-resistant NSCLC cells through EMT, and activated apoptosis through intrinsic and extrinsic apoptotic pathways. Preliminary studies showed that IMB5043 can induce autophagy in H460 and H460/DDP cells, but its specific mechanism has not been further studied. These findings provide a basis for further study of the role of IMB5043 in lung cancer and other malignant tumors and for clinical research on this topic.

Supplementary

The article’s supplementary files as

tcr-14-11-7521-rc.pdf (149.2KB, pdf)
DOI: 10.21037/tcr-2025-1526
tcr-14-11-7521-coif.pdf (682.8KB, pdf)
DOI: 10.21037/tcr-2025-1526
tcr-14-11-7521-supplementary.pdf (224KB, pdf)
DOI: 10.21037/tcr-2025-1526

Acknowledgments

We thank Jianhua Gong (Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China) for providing IMB5043 and H460/DDP cells for this study and all the staff for their help and suggestions on this project.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Footnotes

Reporting Checklist: The authors have completed the MDAR reporting checklist. Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-1526/rc

Funding: This work was supported by the Key Scientific Research Project of North China University of Science and Technology (No. ZD-YG-202312).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-1526/coif). The authors have no conflicts of interest to declare.

Data Sharing Statement

Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-1526/dss

tcr-14-11-7521-dss.pdf (69.6KB, pdf)
DOI: 10.21037/tcr-2025-1526
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    Supplementary Materials

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    tcr-14-11-7521-rc.pdf (149.2KB, pdf)
    DOI: 10.21037/tcr-2025-1526
    tcr-14-11-7521-coif.pdf (682.8KB, pdf)
    DOI: 10.21037/tcr-2025-1526
    tcr-14-11-7521-supplementary.pdf (224KB, pdf)
    DOI: 10.21037/tcr-2025-1526

    Data Availability Statement

    Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-1526/dss

    tcr-14-11-7521-dss.pdf (69.6KB, pdf)
    DOI: 10.21037/tcr-2025-1526
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