From quinoline to cancer therapy: A systematic overview of its biological mechanisms and therapeutic roles

2.1. Search strategy

A systematic review was conducted to evaluate the biological mechanisms and therapeutic applications of quinoline and quinoline-derived compounds in cancer models. A comprehensive search of PubMed, Scopus, and Web of Science databases was performed to identify relevant studies published between January 2019 and April 2025. The search strategy employed the following Boolean query:

(“Quinolines” OR “Quinoline Derivatives”) AND (“Antitumor Activity” OR “Cancer Therapy” OR “Oncology Treatment”). Only articles published in English were considered. In addition, the reference lists of all selected articles were manually screened to retrieve further relevant studies not captured during the initial search.

2.2. Eligibility criteria

Study eligibility was determined based on the population, intervention, comparison, and outcome (PICO) framework:

• Population: Studies involving human cancer cell lines, animal tumor models (e.g., xenograft mouse models), and clinical cancer specimens.

• Intervention: Quinoline and quinoline-derived compounds, including functionalized quinolines, metal complexes, and hybrid molecules.

• Comparison: Standard chemotherapeutic agents (e.g., cisplatin, doxorubicin, oxaliplatin), molecular inhibitors (e.g., Osimertinib, Fulvestrant), or untreated control groups.

• Outcomes: Investigation of biological mechanisms (e.g., apoptosis induction, autophagy regulation, reactive oxygen species (ROS) production, cell cycle arrest), molecular target modulation (e.g., EGFR, Topoisomerase I/II, β-Catenin, mTOR), therapeutic efficacy (e.g., IC₅₀ values, tumor growth inhibition), selectivity, and safety profiles.

Inclusion criteria encompassed original research articles evaluating the anticancer activity of quinoline derivatives and reporting biological mechanisms or therapeutic efficacy. Exclusion criteria included studies focused on non-oncological indications, those lacking appropriate control groups, studies without relevant mechanistic or therapeutic outcomes, reviews, and publications in languages other than English. Studies published prior to 2019 were also excluded.

2.3. Study selection

All records retrieved were exported to Microsoft Excel for duplicate removal. The remaining unique records were then imported into Zotero for reference management and citation formatting.

Two reviewers independently screened the titles and abstracts for relevance. Full-text articles of potentially eligible studies were retrieved and assessed against the inclusion and exclusion criteria. Disagreements were resolved through discussion or consultation with a third reviewer. The study selection process was summarized using a preferred reporting items for systematic reviews and meta-analyses (PRISMA) flow diagram (Figure 1).

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Figure 1.

PRISMA flow diagram.

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2.4. Data extraction

Data were independently extracted using a pre-designed standardized form. Extracted information included the first author’s name, year of publication, study design (in vitro, in vivo, clinical), experimental model (cell line, animal, clinical specimen), specific quinoline derivative used and chemical modifications, cancer type, molecular targets, biological mechanisms explored, therapeutic outcomes (e.g., IC₅₀ values, tumor inhibition rates), and clinical outcomes, if available. Data extraction was independently performed by two reviewers, with disagreements resolved by consensus.

3.1. Apoptosis induction via mitochondrial pathways

Several quinoline-based compounds exert cytotoxic effects through intrinsic (mitochondria-mediated) apoptosis Figure 2. For instance, Tan et al. [13] synthesized spirocyclic 1,3-indanedione-based tetrahydroquinolines and assessed their anticancer activity in A549 lung cancer cells, with IC₅₀ values of 11.82 μM for compound 3c and 19.93 μM for compound 3v. These compounds promoted mitochondrial fragmentation, ROS-induced apoptosis, and S/G2M cell cycle arrest in A549 lung cancer cells (Table S1).

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Figure 2.

Mechanistic pathway of mitochondrial apoptosis.

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Cytotoxicity was measured using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, which confirmed dose-dependent cell death. The apoptotic effects were further characterized by flow cytometry (Annexin V/PI staining), demonstrating the induction of a higher proportion of apoptotic cells. Mechanistic studies revealed mitochondrial membrane potential loss (MMP), identified by JC-1 staining, and reactive oxygen species increase, quantified by the 2′,7′-dichlorodihydrofluorescein diacetate (DCFH-DA) staining. Western blotting demonstrated the activation of key apoptotic proteins, including cleaved caspase-3 and caspase-9, along with an upregulation of pro-apoptotic Bcl-2–associated X protein (Bax) and a downregulation of anti-apoptotic B-cell lymphoma 2 (Bcl-2). RNA sequencing confirmed Instance, Tan et al. [13] synthesized spirocyclic 1,3-indanedione-based tetrahydroquinolines and assessed their anticancer activity in A549 lung cancer cells, with IC₅₀ values of 11.82 μM for compound 3c and 19.93 μM for compound 3v. These compounds promoted mitochondrial fragmentation, ROS-induced apoptosis, and S/G2M cell cycle arrest in A549 lung cancer cells (Table S1).

Cytotoxicity was measured using the MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide) assay, which confirmed dose-dependent cell death. The apoptotic effects were further characterized by flow cytometry (Annexin V/PI staining), demonstrating the induction of a higher proportion of apoptotic cells. Mechanistic studies revealed mitochondrial membrane potential loss (MMP), identified by JC-1 staining, and reactive oxygen species increase, quantified by the 2′,7′-dichlorodihydrofluorescein diacetate (DCFH-DA) staining. Western blotting demonstrated the activation of key apoptotic proteins, including cleaved caspase-3 and caspase-9, along with an upregulation of pro-apoptotic Bcl-2–associated X protein (Bax) and a downregulation of anti-apoptotic B-cell lymphoma 2 (Bcl-2). RNA sequencing confirmed global changes in gene expression, supporting the induction of the pathways of apoptosis. All these methods confirmed the induction of mitochondrial apoptosis by the compounds via ROS generation and mitochondrial damage.

ROS play a crucial role in the anticancer effects of quinoline derivatives. Recent studies have demonstrated that quinoline-based compounds can elevate intracellular ROS levels, leading to mitochondrial dysfunction and activation of the intrinsic apoptotic pathway. Ferreira et al. [14] reviewed quinoline Schiff base derivatives and highlighted their ability to generate ROS, resulting in oxidative stress-mediated cell death in cancer models. Similarly, Zinovkin et al. [15] discussed that stimulation of ROS production or inhibition of antioxidant defenses represents a promising anticancer strategy, particularly when targeting mitochondrial ROS to induce apoptosis selectively in tumor cells. These findings indicate that ROS are not merely byproducts of quinoline action but central mediators amplifying apoptotic signaling. The prooxidant effects of quinoline derivatives may therefore be strategically optimized to overcome resistance mechanisms in cancer cells while minimizing toxicity in normal tissues by controlling ROS generation levels (Table S1).

In this study, cisplatin was used as a reference drug and showed comparable apoptotic induction, but the quinoline derivatives exhibited distinct mitochondrial fragmentation and ROS-mediated mechanisms, suggesting potential advantages in bypassing cisplatin-specific resistance pathways. Furthermore, compared to doxorubicin, which, according to Minotti et al. [16], induces apoptosis mainly through topoisomerase II inhibition and DNA intercalation, leading to dose-limiting cardiotoxicity, these quinoline derivatives act via mitochondrial pathways and ROS generation, potentially offering safer anticancer profiles

Similarly, Živanović et al., 2024 [17] further synthesized 4-aminoquinoline derivatives that induced apoptosis and mitochondrial damage in human pancreatic ductal adenocarcinoma cell line such as MIA Paca 2 and SW1990 pancreatic cell lines, with preliminary safety shown in zebrafish embryos.

All the compounds exhibited strong cytotoxicity with the values of IC₅₀ ranging from nanomolarity to low micromolarity, and the most potent one was compound 1, with a value of 3.78 μM ± 0.32 μM in PANC-1. Flow cytometry confirmed the induction of apoptosis with augmented cell populations of the apoptotic type, while JC-1 staining revealed extensive depopulation of mitochondrial membrane potential, and DCFH-DA staining revealed augmented levels of reactive oxygen species (ROS) and mitochondrial reactive oxygen species (mROS). In addition, the compounds inhibited the induction of autophagy as revealed by augmented microtubule-associated protein 1 light chain 3-II (LC3-II) and sequestosome 1 (SQSTM1/p62) levels and lysosomal dysfunction reflective of lysosomal-associated membrane protein 1 (LAMP1) staining. The dual action inducing apoptosis while inhibiting the induction of autophagy was complemented with in vivo confirmation using zebrafish xenograft model where the compounds inhibited tumor growth and metastasis with low systemic toxicity (LC50 > 60 μM). This study identified 4-aminoquinolines as effective dual-action anti-pancreatic ductal adenocarcinoma (PDAC) agents with good safety.

In this study, cisplatin was also used as a reference and, while effective, it did not exhibit the dual apoptosis–autophagy modulation seen with the quinoline derivatives, highlighting their potential mechanistic superiority. Additionally, compared to doxorubicin, which causes apoptosis predominantly via DNA intercalation and ROS production leading to cardiotoxicity [16], these quinoline compounds induce apoptosis through mitochondrial dysfunction and autophagy inhibition, suggesting different therapeutic advantages.

3.2. Targeting kinase pathways

Quinoline-based compounds have demonstrated strong inhibition of cancer-associated kinases. He et al. [10] synthesized β-methyl-4-acrylamido quinolines that inhibit PI3Kα/β/γ/δ and mTOR, effectively downregulating the protein kinase B (AKT)/mTOR axis (Figure 3), with IC₅₀ values of 0.80 ± 0.15 nM for PI3Kα and 5.0 nM ± 0.39 for mTOR. The compounds were tested on PC3 (prostate cancer) and U87MG (glioblastoma) cell lines, demonstrating potent cytotoxicity GI₅₀: 0.36 ± 0.02 μM for PC3, 0.14 ± 0.03 μM for uppsala 87 malignant glioma (U87MG)). The study utilized kinase inhibition assays, cell proliferation (GI₅₀) assays, Western blotting for pathway analysis, and in vivo xenograft models (U87MG in nude mice), achieving 93.5% tumor growth inhibition at 30 mg/kg.

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Figure 3.

Dual pathways of PI3K/AKT/mTOR and KRAS/ RAF/MEK/ERK in cell proliferation and survival.

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In this study, no standard kinase inhibitor was used as a direct comparator; however, compared to traditional chemotherapeutics like cisplatin, which is commonly used for glioblastoma treatment and, according to Stupp et al. [18], these quinoline-based kinase inhibitors offer a targeted approach via PI3K/mTOR inhibition with nanomolar potency, potentially achieving greater efficacy with lower effective doses and reduced adverse effects.

Tian et al. [6] developed pyrroloquinoline derivatives that target PI3Kα/γ/mTOR with IC₅₀ values of 4 ± 1 nM (PI3Kα), 7 ± 3 nM (PI3Kγ), and 15 ± 6 nM (mTOR). These compounds induced apoptosis via p53 activation and AMP-activated protein kinase (AMPK) upregulation, demonstrated by MTT assays, kinase inhibition, apoptosis induction, and molecular docking, and were tested on LoVo (colorectal), MCF-7 (breast), MDA-MB-231 (breast), HepG2 (liver), A549 (lung), and NCM460 (normal intestinal) cell lines. Although no standard drug was directly used in this study, the nanomolar kinase inhibition observed suggests superior potency compared to conventional chemotherapies such as doxorubicin, which primarily acts through DNA intercalation rather than kinase pathway modulation [16].

Kardile et al. [19] synthesized sulfonamide-linked quinolines targeting epidermal growth factor receptor (EGFR) L858R/T790M mutations, which bind to the EGFR adenosine triphosphate (ATP) and allosteric sites, disrupting downstream signaling in the protein kinase B (AKT) pathway. The compounds were evaluated on HCC827 (EGFR Del E746-A750), H1975 (L858R/T790M), A549 wild-type epidermal growth factor receptor (WT-EGFR), and human bronchial epithelial cell line (BEAS-2B) cell lines, demonstrating potent inhibition (IC₅₀: 0.010 ± 0.02 μM for HCC827, 0.21 ± 0.99 μM for H1975). The dual-site binding confers a strong antitumor effect even in resistant cancer cells. This dual inhibition contrasts with cisplatin’s non-selective DNA damage mechanism and highlights the ability of quinoline-based EGFR inhibitors to overcome resistance mutations such as T790M, a major limitation in standard EGFR-targeted therapies like gefitinib or erlotinib [20].

Complementing these, Zhang et al. [21] reported a CDK8/19 inhibitor that effectively downregulated MYC proto-oncogene (MYC) and reduced tumor burden in acute myeloid leukemia (AML) and colon cancer xenograft models, with high tumor-selective accumulation, showing IC₅₀ values of 3.6 ± 1 nM for CDK8, a Kd of 4.4 ± 1 nM for CDK19, and cytotoxicity IC₅₀ of 0.108 ± 0.012 µM for MV4-11 AML cells. In vivo studies confirmed tumor-selective accumulation and efficacy against CT26 colon cancer xenografts, though IC₅₀ for CT26 in vitro was not reported. The compound inhibits CDK8/19-mediated transcription, leading to the suppression of oncogenes such as MYC, which are critical for cancer cell survival. This was validated on MV4-11 (AML), CT26 (colon), and 293-WT/293-dKO cells using NF-κB reporter assays, xenograft models, and X-ray crystallography for structure validation.

Unlike traditional chemotherapies such as doxorubicin, which cause cytotoxicity by damaging DNA and generating ROS effects linked to cardiotoxicity [16], this quinoline-based CDK inhibitor acts by selectively modulating transcriptional regulation pathways, pointing towards a more targeted and potentially safer anticancer therapy.

Collectively, these findings underscore the therapeutic potential of quinoline derivatives as kinase inhibitors, leveraging multiple mechanisms, including direct kinase inhibition, induction of apoptosis, and transcriptional suppression, to achieve robust anticancer effects across diverse malignancies.

The structure–activity relationship (SAR) analysis of quinoline-based kinase inhibitors indicates that acrylamido groups at position-4 enhance covalent binding to kinase active sites, as seen with β-methyl-4-acrylamido quinolines targeting PI3K/mTOR [10]. In pyrroloquinoline derivatives, the fused pyrrole ring improves π-π interactions within ATP-binding pockets, increasing selectivity [6]. For EGFR inhibitors, sulfonamide linkers improve solubility and dual-site binding, effective against resistant mutations [19]. CDK8/19 inhibitors benefit from planar quinoline cores with amine substitutions for hinge binding. Future optimization could explore linker rigidification and polar substituents to enhance kinase selectivity and pharmacokinetic properties [21].

3.3. Epigenetic modulation

Several studies have demonstrated antitumor effects of certain quinoline analogs via epigenetic reprogramming (Figure 4). In 2024, Zhang et al [7] developed FKL117, as a selective HDAC1 inhibitor that exhibited potent activity with an IC₅₀ value 0.022 ± 0.055 μM in HeLa (cervical cancer). This compound induced histone H3 and H4 acetylation, promoting chromatin relaxation and transcriptional activation of tumor suppressor genes, which led to G2/M arrest (increased cyclin B1, decreased CDC2) and apoptosis (↑Bax, ↓Bcl-2), and significant tumor reduction in HeLa xenograft models. Additionally, its effects were validated in SiHa and C-33A (cervical cancer) cell lines, while showing minimal impact on MiHa (normal hepatocyte) cells, demonstrating cancer selectivity.

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Figure 4.

Epigenetic modulation by HDAsC and BRD4 inhibitors.

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Unlike cisplatin, the standard treatment for cervical cancer that causes DNA crosslinking and systemic toxicity [22], this quinoline-based HDAC inhibitor exerts epigenetic modulation, potentially offering a more targeted and safer therapeutic approach.

The antitumor effects were confirmed through MTT assays, Western blotting, flow cytometry for apoptosis, colony formation assays, and in vivo xenograft models in nude mice, where significant tumor reduction was observed without toxicity to major organs.

Yu et al. [23] designed an (R)-imidazo[4,5-c] quinolinyl-isoxazole derivative as a selective bromodomain and extra-terminal (BET) inhibitor targeting BRD4, effectively suppressing c-Myc expression in acute myeloid leukemia (AML). The compound demonstrated strong binding affinity (IC₅₀: 1.9 nM for Bromodomain-containing protein 4 (BRD4), 190 nM for MV4-11 cells) and induced G0/G1 cell cycle arrest and apoptosis, validated by flow cytometry and Western blotting for Cellular myelocytomatosis oncogene (c-Myc), cyclin dependent kinase 6 (CDK6), poly(ADP-ribose) polymerase (PARP), and p21. When tested across several cancer cell lines, MV4-11, MOLM-13, Jurkat, and MM.1S, it achieved 70.4% tumor growth inhibition (TGI) in Human myelomonocytic leukemia cell Line (MV4-11) xenografts at a dose of 50 mg/kg, demonstrating excellent oral bioavailability (114%). This compound outperformed JQ-1, a well-known bromodomain and extra-terminal (BET) inhibitor, in both potency and pharmacokinetic profile, positioning it as a highly promising lead candidate for AML treatment. Compared to standard AML chemotherapeutics such as cytarabine, which causes myelosuppression and neurotoxicity [24], this quinoline-based BET inhibitor offers a novel epigenetic mechanism with potentially fewer systemic side effects.

Joshi et al. [25] developed dual HDAC/topoisomerase inhibitors showing efficacy in EGFR-resistant non-small cell lung cancer (NSCLC). These compounds were tested in vitro against various cancer cell lines, including A549 (lung), H1299 (lung), MDA-MB-231 (breast), MCF-7 (breast), HT-29 (colon), and H1975 (EGFR mutant lung cancer), while normal cell lines Human embryonic kidney 293 (HEK193), Peripheral Blood mononuclear cells (PBMCs), and the immortalized clonal line of rat ventricular cardiomyoblasts (H9c2) were used to assess toxicity. Compound 5c demonstrated high potency with an IC₅₀ of <1 µM in A549 cells and <250 nM in H1975 cells.

Mechanistic studies confirmed that these compounds achieved dual inhibition of topoisomerases (Topo I/II), validated using decatenation and relaxation assays, while selectively inhibiting HDAC1, HDAC6, and HDAC8, as shown by isoform profiling (IC₅₀ values). Docking studies (in silico) demonstrated strong binding of compound 5c to hTopoIIα and HDAC1/6/8 active sites, supporting its dual-targeting nature. In 2D and 3D culture models, the compounds effectively reduced cancer cell proliferation. Flow cytometry analysis revealed the induction of ROS using DCFH-DA staining, and mitochondrial membrane potential disruption detected by JC-1(5,5’,6,6’-tetrachloro-1,1’,3,3’-tetraethylbenzimidazolylcarbocyanine iodide) staining. Western blotting and real time pcr were used to assess the modulation of target proteins, while the absence of DNA intercalation was confirmed.

In vivo, compound 5c effectively reduced tumor growth in an A549 xenograft model in nude mice, achieving 67% tumor inhibition at a dose of 15 mg.kg^-1 and 84% at 30 mg.kg^-1. Importantly, it showed no harmful effects on normal cells (HEK-293, H9c2, PBMCs). These results highlight compound 5c as a promising multi-target anticancer agent, combining strong efficacy with low toxicity.

Unlike cisplatin, which remains a standard therapy for NSCLC but causes dose-limiting nephrotoxicity [26], this quinoline-based dual HDAC/topoisomerase inhibitor targets epigenetic and DNA topology pathways with promising safety profiles.

Finally, Hauguel et al. [27] reported quinoline-2-carbonitrile-based hydroxamic acids that act as dual tubulin polymerization and HDAC inhibitors, triggering apoptosis in multiple cancer models.

These compounds were tested on HCT116 (IC₅₀: 0.5 ± 0.002 nM), HT-29 (resistant, IC₅₀: 0.6 ± 0.003 nM), K562R (MDR, sub-nM), A549, MCF-7, and MCA205 cell lines, where they induced G2/M arrest, mitochondrial depolarization, and caspase-dependent apoptosis. They showed strong, selective inhibition of HDAC8 (IC₅₀: 150–280 nM ) and disrupted tubulin polymerization, which is essential for cell division. Mechanistically, they also interfered with DNA repair, indicated by increased γH2AX, a marker of DNA damage.

In vivo, compound 12a achieved 70% tumor regression at 0.5 mg. kg^-1 (intratumoral) in an MCA205 fibrosarcoma model without systemic toxicity, demonstrating strong potential for clinical development. Compared to doxorubicin, which inhibits topoisomerase II and intercalates DNA, causing cardiotoxicity [28], these quinoline-based compounds exert dual HDAC and tubulin inhibition with potentially improved safety and multitarget efficacy.

SAR analyses of quinoline-based epigenetic modulators have revealed that hydroxamic acid groups are crucial for HDAC inhibition due to their Zn²⁺ chelating ability [7], while the quinoline cap contributes to isoform selectivity. In the case of BRD4 inhibitors, Yu et al. [23] demonstrated that the imidazo[4,5-c]quinoline scaffold fits effectively within the acetyl-lysine binding pocket, with isoxazole substituents enhancing compound stability. For dual HDAC/topoisomerase inhibitors, Joshi et al. [25] reported that incorporating a planar quinoline core facilitates DNA intercalation. Further structural optimization, such as adjusting linker lengths or adding electron-donating groups, could potentially enhance potency and selectivity while minimizing off-target interactions.

3.4. DNA intercalation and damage response

Quinoline derivatives have also been shown to interfere with nuclear function through direct DNA interaction, triggering replication stress or cell cycle arrest.

Hu et al. [12] investigated copper-quinoline-thiosemicarbazone complexes, specifically Complex 1: [Cu(qcpt)(PPh₃)₂Br]·2CH₃CN and Complex 2: [Cu₂(qcapt)(Ac)₂(CH₃OH)], which exhibited potent anticancer activity across several cancer cell lines, including SMMC7721 (liver), HCT116 (colorectal), HT-29 (resistant colorectal), and TFK-1 (bile duct The researchers found that both complexes could intercalate DNA (Kapp ≈ 4 × 10⁶ M⁻¹), generate ROS, cause calcium overload, and disrupt mitochondrial function, ultimately leading to apoptosis. Notably, Complex 1 showed an IC₅₀ of 1.58 ± 0.26 μM in SMMC7721 cells, making it more potent than cisplatin. Flow cytometry confirmed S-phase cell cycle arrest and apoptosis, with a significant increase in apoptotic cells at 29.5% (2.5 µM) and 62.8% (5 µM). This dual action directly damages DNA damage and mitochondrial disruption highlights the strong therapeutic potential of these complexes.

In this study, cisplatin was used as a reference and, while effective, it did not show the combined mechanism of DNA intercalation and mitochondrial disruption observed with these copper-quinoline complexes, suggesting potential for overcoming cisplatin resistance mechanisms [29].

Zhou et al. [8] explored various quinoline-based compounds with methylamine and methylpiperazine substitutions on rings B, C, and D, including compounds 6, 8, 9, 11, 12, and 13, tested on A549 (lung cancer), U2OS (osteosarcoma), and MCF-7 (breast cancer) cell lines. The study demonstrated that these derivatives could inhibit multiple DNA-modifying enzymes, including DNA methyltransferase 1 (DNMT1), glycosylated ber, and polymerases, while also intercalating DNA. Mechanistically, these compounds triggered DNA damage via the activation of the p53 pathway, upregulating p21 and γH2AX, which are key markers of DNA damage response. Compound 11 displayed selective cytotoxicity in A549 cells, where it induced p53-dependent DNA damage, making it a promising agent for targeting cancers with functional p53. Compared to doxorubicin, which intercalates DNA and poisons topoisomerase II, leading to oxidative stress and mitochondrial dysfunction [30], these quinoline derivatives additionally inhibit DNA-modifying enzymes, potentially enhancing their anticancer efficacy while reducing cardiotoxicity risk.

Mingoia et al. [31] synthesized a series of 1,3,4-substituted pyrrolo[3,2-c]quinoline derivatives, which were evaluated for their antiproliferative activity across a wide range of cancer cell lines, including MCF-7 (breast), MDA-MB-231 (triple-negative breast), LAN-5 (neuroblastoma), HeLa (cervical cancer), H292 (lung cancer), and 16HBE (normal epithelial cells). Among these, compound 4g, which contains a benzodioxol group, was the most potent, showing strong cytotoxicity showing strong cytotoxicity with activity in the low micromolar range across five cancer models (10 μM is the tested dose for screening NCI (one-dose assay). Mechanistic studies revealed that compound 4g induced S-phase cell cycle arrest, increased ROS production, and triggered apoptosis. Docking studies confirmed that these compounds interact with heat shock protein 90 (HSP90) and estrogen receptors (ER), two key cancer targets. Importantly, compound 4g exhibited low toxicity towards normal cells, highlighting its promise as a safe and effective anticancer agent. Unlike cisplatin, which induces apoptosis predominantly via DNA crosslinking and activates p53-mediated pathways but is limited by nephrotoxicity and neurotoxicity [32], this quinoline derivative combines DNA intercalation with protein target modulation, potentially offering multi-target anticancer effects with improved safety profiles.

3.5. Autophagy modulation

Various quinoline derivatives influence tumor cell survival via autophagy regulation.

Liang et al. [9] studied a series of bivalent quinoline derivatives with 4-6 methylene spacers between a phenoxy group (position-7) and various substituents (position-4). These compounds were tested on multiple cancer cell lines, including HCT116 (colorectal, IC₅₀: 0.26 μM), A549 (lung, IC₅₀: 2.75 μM), HepG2 (liver, IC₅₀: 31.5 μM), BGC-823 (gastric, IC₅₀: 4.06 μM), HeLa (cervical, IC₅₀: 3.71 μM), and MCF-7 (breast, IC₅₀: 3.08 μM). Among them, compound 4b demonstrated the strongest antitumor activity, and mechanistic studies indicated that it inhibited cancer growth by inducing autophagy via the autophagy-related 5 (ATG5)/autophagy-related 7 (ATG7) pathway rather than triggering apoptosis (Figure 5).

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Figure 5.

ATG5/ATG7-dependent autophagosome formation pathway.

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Mechanistic studies revealed that 4b promoted autophagy through the ATG5/ATG7 pathway without triggering apoptosis or ferroptosis. Western blotting showed increased levels of autophagy markers (LC3-II, Beclin-1), while CRISPR-Cas9 knockout of ATG5 or ATG7 eliminated the compound’s cytotoxic effect, confirming its dependence on autophagy. In vivo, compound 4b achieved an 81.76% reduction in tumor size in a HeLa xenograft model in BALB/c mice at 8 mg/kg, with no significant toxicity, highlighting its potential as a safe autophagy inducer. Unlike cisplatin, which primarily induces apoptosis through DNA crosslinking and often results in nephrotoxicity and neurotoxicity as dose-limiting toxicities [33], compound 4b promotes autophagy-dependent cell death, representing a mechanistically distinct therapeutic approach that may bypass resistance to conventional chemotherapies.

Similarly, Shen et al. [34] explored Cu (II)-quinoline Schiff base complexes (Cu1, Cu2, Cu3) for their ability to trigger autophagy in cancer cells, including SK-OV-3 (ovarian), T24 (bladder), HepG2 (liver), and MGC80-3 (gastric), with low toxicity towards normal cells (WI-38 and HL-7702). Among these, Cu1 and Cu2 displayed superior activity, with IC₅₀ values of 9.7 ± 0.5 μM and 9.6 ± 0.9 μM, respectively, surpassing cisplatin (12.2 ± 0.6 μM). The compounds induced autophagy by causing ER stress and ROS generation, with Western blot confirming the upregulation of ER stress markers (GRP78, CHOP) and activation of the PERK-eIF2α-ATF4 pathway. Mechanistically, the Cu (II) complexes were reduced to Cu(I) by intracellular GSH, generating OH via a Fenton-like reaction, which led to mitochondrial depolarization (detected by JC-1 staining), Ca²⁺ overload, and ROS generation. These processes triggered apoptosis through caspase-3 and caspase-9 activation. In vivo, Cu1 and Cu2 reduced tumor growth in a SK-OV-3 xenograft model by 48% and 58%, respectively, demonstrating their efficacy as selective chemodynamic therapy agents. Compared to cisplatin, which acts mainly through direct DNA crosslinking without affecting autophagy pathways [35], these copper-quinoline complexes combine autophagy induction with ROS-mediated mitochondrial dysfunction, potentially enhancing anticancer efficacy while circumventing platinum resistance.

In addition, Li et al. [36] synthesized 4,7-disubstituted quinoline derivatives, with compound 10k (3-nitrophenyl and 3,4,5-trimethoxybenzyl groups) showing the most potent activity. This compound was test against various cancer cell lines, including HCT116 (colorectal), HepG2 (liver), BGC823 (gastric), A549 (lung), and A2780 (ovarian), with significantly lower toxicity towards normal cells (FHC - normal colon, 293T - normal kidney). Compound 10k exhibited strong cytotoxicity, with IC₅₀ values of 0.35 µM (HCT116), 1.98 µM (HepG2), 0.60 µM (BGC823), 0.39 µM (A549), and 0.67 µM (A2780). Mechanistic studies confirmed that 10k induced autophagy by stabilizing ATG5, increasing LC3-II conversion, and promoting autophagosome formation, as observed through mCherry-EGFP-LC3B fluorescence and transmission electron microscopy (TEM). Unlike many anticancer agents, 10k did not cause apoptosis, as shown by the absence of caspase-3 activation. In vivo, 10k significantly suppressed tumor growth in a CT26 colorectal cancer xenograft model, highlighting its potential as an autophagy-based anticancer agent. In contrast, doxorubicin induces apoptosis via topoisomerase II inhibition and ROS generation but is associated with dose-dependent cardiotoxicity [30], whereas compound 10k exerts its anticancer effect through autophagy induction, potentially minimizing systemic toxicity and providing a novel mechanism to overcome resistance to pro-apoptotic drugs.

Recent advances in the classification of cell death have revealed that multiple pathways, such as oxidative stress, apoptosis, and autophagy, can work together to create hybrid forms of cell death. An example of this is oxiapoptophagy, a process observed with thymoquinone [37]. While most studies included in this review focus on the conventional cytotoxic actions of quinoline derivatives, the fact that these compounds can simultaneously increase ROS levels, trigger apoptosis, and modulate autophagy suggests they might also induce similar hybrid types of cell death. Exploring these possibilities further could lead to innovative therapeutic approaches by targeting several weaknesses within cancer cells at once and potentially overcoming treatment resistance.

3.6. Ferroptosis activation

Quinoline-metal hybrids have been shown to trigger ferroptosis, a form of regulated cell death driven by iron-dependent lipid peroxidation (Figure 6). Wang et al. [38] synthesized a series of cycloplatinated (II) complexes (Pt-1 to Pt-4) based on isoquinoline alkaloid ligands to target triple-negative breast cancer (TNBC). The study identified Pt-3, a cycloplatinated complex, as the most potent compound. It was tested across multiple cancer cell lines, including MDA-MB-231 (TNBC), MCF-7 (breast), A549 (lung), A549/CDDP (cisplatin-resistant lung), and WI-38 (normal lung fibroblasts). Notably, Pt-3 demonstrated strong cytotoxicity in TNBC cells, with an IC₅₀ of 2.24 µM in MDA-MB-231, significantly outperforming cisplatin (IC₅₀: 9.86 µM in the same model) and showing a lower resistance factor (RF: 1.44 for Pt-3 vs 7.12 for cisplatin).

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Figure 6.

The mechanisms of ferroptosis.

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Mechanistically, Pt-3 triggered ferroptosis through a process known as ferritinophagy-dependent ferroptosis, where it selectively induced autophagy of ferritin (an iron storage protein) in cancer cells, leading to increased intracellular iron release. Western blot analysis confirmed this mechanism, with a significant reduction in GPX4 (glutathione peroxidase 4), which is a key inhibitor of ferroptosis, alongside increased LC3-II (autophagy marker) and decreased p62 (autophagy substrate). This was further validated by an increase in ROS Table S1 [43], lipid peroxidation (LPO), and malondialdehyde (MDA) levels [44-96]. Confocal microscopy also revealed the formation of autophagic vacuoles, while degradation of ferritin heavy chain (FTH) further supported the ferritinophagy pathway.

In vitro assays, including MTT and inductively coupled plasma mass spectrometry (ICP-MS) for metal uptake, confirmed the selective cytotoxicity of Pt-3 in cancer cells, with minimal effects on normal WI-38 fibroblasts, highlighting its selectivity. The compound also showed a high lipophilicity (log P), which enhanced cellular uptake via an energy-dependent nonendocytic mechanism. In vivo, Pt-3 demonstrated strong antitumor activity in an MDA-MB-231 xenograft mouse model, achieving 65.3% tumor inhibition, significantly superior to cisplatin (43.1%). Importantly, Pt-3 showed a favorable safety profile, with no significant body weight loss or acute toxicity observed in treated mice.

Pt-3 showed strong, selective toxicity against cancer cells with minimal effects on normal WI-38 fibroblasts. Its high lipophilicity enhanced cellular uptake, confirmed by ICP-MS. In an MDA-MB-231 xenograft model, Pt-3 achieved 65.3% tumor inhibition, outperforming cisplatin (43.1%), with no significant toxicity in treated mice. These results highlight Pt-3 as a promising anticancer agent for TNBC, combining ferritinophagy-dependent ferroptosis and ROS generation with excellent safety.

Unlike doxorubicin, which intercalates DNA and inhibits topoisomerase II but faces limitations due to multidrug resistance mechanisms mediated by P-glycoprotein overexpression [39], Pt-3 acts through ferroptosis and autophagy pathways. This unique mechanism could help bypass common multidrug resistance and provide strong anticancer effects with better safety.

According to Wang et al. [38], the SAR analysis showed that cyclometalating the isoquinoline ligand greatly improved the anticancer activity of these complexes compared to their non-cyclometalated forms. The isoquinoline structure itself increased both lipophilicity and stability, leading to better cellular uptake and higher ROS production, which are key factors in triggering ferroptosis. Among the compounds, Pt-3 stood out with superior efficacy, attributed to its optimized electronic structure that promotes metal-to-ligand charge transfer (MLCT) and enhances ferritinophagy-dependent ferroptosis. These results indicate that further modifications, such as adding electron-withdrawing groups to adjust MLCT properties or attaching tumor-targeting units, could further improve their potency and selectivity while maintaining a good safety profile.

3.7. Emerging oncogenic pathways

Researchers are now developing new quinoline derivatives that precisely target specific signaling pathways, offering precise and selective anticancer effects.

Bae et al. [40] introduced a series of 3-(quinolin-2-ylmethylene)-4,6-dimethyl-5-hydroxy-7-azaoxindole derivatives, identifying compound 6–15 as the most effective. This compound was tested on various cancer cell lines, including MCF-7 (2.0 ± 1.6 μM), MDA-MB-231 (2.8 ± 2.3 μM), HT-29 (4.6 ± 2.5 μM), DU145 (1.1 ± 1.2 μM), U937 (6.7 ± 1.9 μM), A549 (4.2 ± 1.9 μM), and PANC-1 (4.0 ± 0.1 μM), as well as normal cell lines CHO-K1 (hamster ovarian) and HEK293 (human kidney). Compound 6–15 exhibited potent cytotoxicity in PANC-1 cells, with a high selectivity index (CHO-K1/PANC-1 = 13.6), indicating strong selectivity for cancer cells over normal cells.

Mechanistically, this compound selectively blocked the Gas6-Axl signaling axis, a key pathway in cancer progression (Figure 7). Western blot analysis confirmed downregulation of Gas6, Axl, and p-Akt, while increasing the Bax/Bcl-2 ratio, indicative of apoptosis induction. The compound triggered apoptosis without direct inhibition of Axl kinase, as shown in cell-free assays. In vivo, 6–15 significantly reduced tumor growth in A549 (lung) and PANC-1 (pancreatic) xenograft models, outperforming standard treatments like cisplatin for lung cancer and gemcitabine for pancreatic cancer. Treated mice showed 100% survival, compared to 80% with gemcitabine. These results establish compound 6–15 as a potent and selective inhibitor of the Gas6-Axl axis with strong antitumor potential.

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Figure 7.

Gas6-Axl signaling axis in cancer.

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In a similar approach, Xu et al. [11] designed a series of thieno[2,3-b] quinoline-procaine hybrids, identifying compound 3b as the most potent. These hybrids were developed as allosteric activators of Src homology region 2 domain-containing phosphatase-1 (SHP-1), a non-receptor protein tyrosine phosphatase that negatively regulates the STAT3 signaling pathway, which is often overactive in cancer. Compound 3b was tested on lymphoma cell lines OCI-Ly10 and SU-DHL-2 (ABC-DLBCL) and was shown to selectively activate SHP-1, increasing its enzymatic activity (EC₅₀: 5.48 ± 0.28 μM for 3b). This activation disrupted the STAT3 signaling pathway, as evidenced by a significant reduction in phospho-STAT3 (p-STAT3) levels, leading to dose-dependent apoptosis in both lymphoma cell lines. Detailed structural studies (CETSA, molecular docking, and MD simulations) showed that 3b binds allosterically to SHP-1, stabilizing its active form.

In vivo, compound 3b significantly inhibited tumor growth in a SU-DHL-2 xenograft model, with no significant toxicity in treated mice. Unlike conventional chemotherapies that act by inducing direct DNA damage or cell cycle arrest, 3b works by restoring the tumor-suppressive function of SHP-1 and downregulating signal transducer and activator of transcription 3 (STAT3) signaling, offering a mechanistically distinct and potentially safer approach for treating activated B-cell–like diffuse large B-cell lymphoma (ABC-DLBCL) [41].

These findings mark the first validation of SHP-1 activation alone as a therapeutic strategy in ABC-DLBCL, making 3b a promising candidate for further development.

3.8. Experimental strategies: From in silico to in vivo

Ramasamy et al. [42] conducted an extensive in-silico study of 8-nitroquinoline hydrazides, a class of quinoline derivatives, to assess their potential as anticancer agents targeting multiple cancer-associated proteins, including EGFR (epidermal growth factor receptor), PI3K (Phosphoinositide 3-Kinase), and CDK2 (Cyclin-Dependent Kinase 2). The study was entirely computational, using advanced computational techniques like density functional theory (DFT), ADME/Tox (absorption, distribution, metabolism, excretion, toxicity) predictions, and molecular docking against 11 oncogenic proteins.

The screened compounds, designated as 6a, 6b, and 6c, shared a common core structure of 2-cyano-N′-(8-nitroquinolin-4-ylidene) acetohydrazide, but differing at position 6.

Among these, compound 6c, which has a methyl group, demonstrated the best pharmacological profile. Docking studies revealed that 6c has strong binding affinity to CDK2 (binding energy: –8.7 kcal.mol^-1) and PI3K (binding energy: –7.5 kcal/mol), surpassing the binding strength of the reference drug doxorubicin. Binding interactions were characterized by stable π–π stacking, hydrogen bonding, and hydrophobic interactions at the active sites of the target proteins. Structural analysis using DFT confirmed that 6c had favorable electronic properties (highest occupied molecular orbital–lowest unoccupied molecular orbital (HOMO–LUMO) energy gaps), which support strong interactions with these proteins.

The compound’s absorption, distribution, metabolism, excretion, and toxicity (ADMET) profile was also evaluated using SwissADME and ProTox-3.0, revealing good oral bioavailability (compliant with Lipinski’s Rule of Five) and low predicted toxicity (LD₅₀: 1000 mg.kg^-1). Although it is well-absorbed in the gastrointestinal (GI) tract, it is unlikely to cross the blood-brain barrier (BBB), which minimizes the risk of central nervous system (CNS) toxicity. The compound also showed minimal inhibition of CYP1A2, indicating low potential for drug-drug interactions.

Overall, compound 6c demonstrated strong binding to two critical cancer-related proteins (CDK2 and PI3K), a favorable safety profile, and good oral bioavailability. These findings highlight the potential of 6c as a promising anticancer lead compound for further in vitro and in vivo evaluations.

Selected compounds are validated using traditional 2D monolayer assays, which have been demonstrated by Tan et al. [13] on A549 lung cancer cells and Zhang et al. [7]on HeLa cells. 3D spheroid models are used to better mimic tumor complexity, as exemplified by Patel et al. [43] in glioblastoma assays. Effective compounds are subsequently advanced to in vivo validation using animal models; for example, Živanović et al. [17] validated the pro-apoptotic effects of 4-aminoquinoline derivatives in zebrafish xenografts, and Liang et al. [9] demonstrated autophagy-mediated tumor inhibition using compound 4b in HeLa xenografts. This multi-step strategy enhances the translational potential of quinoline derivatives for future clinical use (Table S1) [6-13, 17, 19, 23, 25, 27, 31, 34, 36, 38, 40, 42-96].

While quinoline-based compounds demonstrate multi-target anticancer potential, translational application remains limited by the predominant use of 2D models and the scarcity of pharmacokinetic and toxicity evaluations. Future studies should prioritize advanced 3D culture systems, in vivo validations, and comprehensive ADMET profiling to bridge the gap between preclinical findings and clinical translation.