Encapsulation of Nedaplatin in Novel PEGylated Liposomes Increases Its Cytotoxicity and Genotoxicity against A549 and U2OS Human Cancer Cells

Following the discovery of cisplatin over 50 years ago, platinum-based drugs have been a widely used and effective form of cancer therapy, primarily causing cell death by inducing DNA damage and triggering apoptosis. However, the dose-limiting toxicity of these drugs has led to the development of second and third generation platinum-based drugs that maintain the cytotoxicity of cisplatin but have a more acceptable side-effect profile. In addition to the creation of new analogs, tumor delivery systems such as liposome encapsulated platinum drugs have been developed and are currently in clinical trials. In this study, we have created the first PEGylated liposomal form of nedaplatin using thin film hydration. Nedaplatin, the main focus of this study, has been exclusively used in Japan for the treatment of non-small cell lung cancer, head and neck, esophageal, bladder, ovarian and cervical cancer. Here, we investigate the cytotoxic and genotoxic effects of free and liposomal nedaplatin on the human non-small cell lung cancer cell line A549 and human osteosarcoma cell line U2OS. We use a variety of assays including ICP MS and the highly sensitive histone H2AX assay to assess drug internalization and to quantify DNA damage induction. Strikingly, we show that by encapsulating nedaplatin in PEGylated liposomes, the platinum uptake cytotoxicity and genotoxicity of nedaplatin was significantly enhanced in both cancer cell lines. Moreover, the enhanced platinum uptake as well as the cytotoxic/antiproliferative effect of liposomal nedaplatin appears to be selective to cancer cells as it was not observed on two noncancer cell lines. This is the first study to develop PEGylated liposomal nedaplatin and to demonstrate the superior cell delivery potential of this product.

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Decreased accumulation as a mechanism of resistance to cisdiamminedichloroplatinum(II) in human non-small cell lung cancer cell lines: Relation to DNA damage and repair

Lung Cancer ◽

10.1016/0169-5002(91)90105-f ◽

1991 ◽

Vol 7 (3) ◽

pp. 183-184

Keyword(s):

Lung Cancer ◽

Dna Damage ◽

Small Cell Lung Cancer ◽

Cell Lines ◽

Cancer Cell ◽

Cell Lung Cancer ◽

Small Cell ◽

Lung Cancer Cell ◽

Small Cell Lung ◽

Dna Damage And Repair

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Recombinant human interleukin-4 inhibits growth of some human lung tumor cell lines in vitro and in vivo

Blood ◽

10.1182/blood.v82.9.2837.2837 ◽

1993 ◽

Vol 82 (9) ◽

pp. 2837-2844 ◽

Cited By ~ 39

Author(s):

MS Topp ◽

M Koenigsmann ◽

A Mire-Sluis ◽

D Oberberg ◽

F Eitelbach ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Line ◽

Cell Lines ◽

Cancer Cell ◽

Cell Lung Cancer ◽

Small Cell ◽

Lung Cancer Cell ◽

Small Cell Lung

Abstract Cytokines play an important role in activating the immune system against malignant cells. One of these cytokines, interleukin-4 (IL-4) has entered clinical phase I trials because of its immunoregulatory potency. In the present study we report that recombinant human (rh) IL- 4 has major direct antiproliferative effects on one human lung cancer cell line (CCL 185) in vitro as measured by a human tumor cloning assay (HTCA), tritiated thymidine uptake, and counting cell numbers and marginal activity in a second cell line (HTB 56) in the HTCA. This activity could be abolished by neutralizing antibody against rhIL-4. The biological response of the tumor cells to the cytokine is correlated with expression of receptors for human IL-4 on both the mRNA level and the protein level. The responsive cell line, CCL 185, secretes IL-6 after being incubated with rhIL-4. On the other hand, neutralizing antibodies against IL-6 showed no influence on the growth modulatory efficacy of rhIL-4 in this cell line. Furthermore, CCL 185 does not show detectable production of IL-1, tumor necrosis factor alpha or interferon gamma after incubation with rhIL-4. Thus, the response to rhIL-4 is not mediated through autocrine production of these cytokines triggered by rhIL-4. In a next series of experiments some of the cell lines were xenotransplanted to BALB/c nu/nu mice. Subsequently, the mice were treated for 12 days with two doses of 0.5 mg/m2 rhIL-4 or control vehicle subcutaneously per day. Treatment with rhIL-4 yielded a significant inhibition of tumor growth versus control in two of the non-small cell lung cancer cell lines being responsive in vitro (CCL 185, HTB 56). Histology of the tumors in both groups showed no marked infiltration of the tumors with murine hematopoietic and lymphocytic cells consistent with the species specificity of IL-4. In contrast, no tumor growth inhibition was found in the small cell lung cancer cell lines (HTB 119, HTB 120) being nonresponsive in vitro. We conclude that rhIL-4 has direct antiproliferative effects on the growth of some human non-small cell lung cancer cell lines in vitro and in vivo, which together with its regulatory effects on various effector cell populations makes this cytokine an interesting candidate for further investigation in experimental cancer treatment.

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Antifungal imidazole: Potential new antineoplastic agent-cytotoxic effects on non-small cell lung cancer cell lines (A549).

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e21037 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e21037-e21037

Author(s):

Erkan Kahraman ◽

Erdem Goker

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cancer Cells ◽

Cell Lines ◽

Cancer Cell ◽

Cell Lung Cancer ◽

Colony Formation ◽

A549 Cells ◽

Small Cell ◽

Small Cell Lung

e21037 Background: There are many drugs that can be applied to the treatment of lung cancer. These therapeutics include classical chemotherapeutics, targeted drugs against driver mutations, and immunotherapeutics. However, still, new agents are required to better results and patients outcomes. Recently, imidazole and its compounds, a type of antifungal drugs, were found to have antitumor efficacy in several cancer types. Its effects on non-small-cell lung cancer cells are yet known. This study aimed to detect anti-cancer properties of imidazole on non-small-cell lung cancer cells and suitability for clinical usage as an anti-cancer agent. Methods: We used A549 cell lines that are non-small-cell lung cancer cells in this study. A549 cells were treated with imidazole (molecular grade) at 1, 5, 10, 20, 40, 80 mM doses for 24, 48 and 72 hours. Cytotoxicity and IC50 values (the half-maximal inhibitory concentration) were calculated using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) analysis. Colony formation assay was performed to detect the effect of imidazole on cancer cell colony formation ability. The cellular morphological alterations were observed on bright-field microscopy using Giemsa staining. Cellular migration status of A549 cells was defined with in vitro scratch assay up to 48th hour. Results: Cytotoxicity assay results showed that low-level imidazole induced cell proliferation. However, high-level imidazole treatment decreased the cell viability of A549 cells in a dose and time-dependent manner. The IC50 value was calculated as 60 mM, 28 mM, and 15,9 µM doses respectively at 24, 48, 72 hours in A549 cells. Also, we determined that the number of colonies (number of colonies: 42.7 ± 3.06) formed in A549 cell lines treated with imidazole at IC50 dose was statistically less than the colony number of the control group (number of colonies: 70.7 ± 5.13) (p < 0.01). Interestingly, we observed that colony number increased at a low dose (at 5 mM) imidazole treated group, statistically significant (p < 0.05). Cellular morphology was not affected at low doses; however, at the IC50 dose, A549 cells changed their cellular morphology, lost cell-cell contact, decreased cytoplasmic volume, and differentiated from parental morphology. In addition to these effects, we observed that imidazole treated cells decreased their migration capabilities compared with control group cells (p < 0.05). Conclusions: Our results have shown that antifungal imidazole treatment inhibits cancer cell biological responses such as proliferation, colony formation ability, and motility in non-small lung cancer cell lines in a dose and time-dependent manner. These results suggest that imidazole would be the right candidate for the synergy with other therapeutic options such as immunotherapy. This introductory study allows us further studies exploring the synergy and its mechanism.

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Recombinant human interleukin-4 inhibits growth of some human lung tumor cell lines in vitro and in vivo

Blood ◽

10.1182/blood.v82.9.2837.bloodjournal8292837 ◽

1993 ◽

Vol 82 (9) ◽

pp. 2837-2844

Author(s):

MS Topp ◽

M Koenigsmann ◽

A Mire-Sluis ◽

D Oberberg ◽

F Eitelbach ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Line ◽

Cell Lines ◽

Cancer Cell ◽

Cell Lung Cancer ◽

Small Cell ◽

Lung Cancer Cell ◽

Small Cell Lung

Cytokines play an important role in activating the immune system against malignant cells. One of these cytokines, interleukin-4 (IL-4) has entered clinical phase I trials because of its immunoregulatory potency. In the present study we report that recombinant human (rh) IL- 4 has major direct antiproliferative effects on one human lung cancer cell line (CCL 185) in vitro as measured by a human tumor cloning assay (HTCA), tritiated thymidine uptake, and counting cell numbers and marginal activity in a second cell line (HTB 56) in the HTCA. This activity could be abolished by neutralizing antibody against rhIL-4. The biological response of the tumor cells to the cytokine is correlated with expression of receptors for human IL-4 on both the mRNA level and the protein level. The responsive cell line, CCL 185, secretes IL-6 after being incubated with rhIL-4. On the other hand, neutralizing antibodies against IL-6 showed no influence on the growth modulatory efficacy of rhIL-4 in this cell line. Furthermore, CCL 185 does not show detectable production of IL-1, tumor necrosis factor alpha or interferon gamma after incubation with rhIL-4. Thus, the response to rhIL-4 is not mediated through autocrine production of these cytokines triggered by rhIL-4. In a next series of experiments some of the cell lines were xenotransplanted to BALB/c nu/nu mice. Subsequently, the mice were treated for 12 days with two doses of 0.5 mg/m2 rhIL-4 or control vehicle subcutaneously per day. Treatment with rhIL-4 yielded a significant inhibition of tumor growth versus control in two of the non-small cell lung cancer cell lines being responsive in vitro (CCL 185, HTB 56). Histology of the tumors in both groups showed no marked infiltration of the tumors with murine hematopoietic and lymphocytic cells consistent with the species specificity of IL-4. In contrast, no tumor growth inhibition was found in the small cell lung cancer cell lines (HTB 119, HTB 120) being nonresponsive in vitro. We conclude that rhIL-4 has direct antiproliferative effects on the growth of some human non-small cell lung cancer cell lines in vitro and in vivo, which together with its regulatory effects on various effector cell populations makes this cytokine an interesting candidate for further investigation in experimental cancer treatment.

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SCLC-J1, a novel small cell lung cancer cell line

Biochemistry and Biophysics Reports ◽

10.1016/j.bbrep.2021.101089 ◽

2021 ◽

Vol 27 ◽

pp. 101089

Author(s):

Kazuo Ohara ◽

Shintaro Kinoshita ◽

Jun Ando ◽

Yoko Azusawa ◽

Midori Ishii ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Line ◽

Cancer Cell ◽

Cell Lung Cancer ◽

Cancer Cell Line ◽

Lung Cancer Cell Line ◽

Small Cell ◽

Lung Cancer Cell ◽

Small Cell Lung

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Small-molecule inhibition of APE1 induces apoptosis, pyroptosis, and necroptosis in non-small cell lung cancer

Cell Death and Disease ◽

10.1038/s41419-021-03804-7 ◽

2021 ◽

Vol 12 (6) ◽

Author(s):

Kaili Long ◽

Lili Gu ◽

Lulu Li ◽

Ziyu Zhang ◽

Enjie Li ◽

...

Keyword(s):

Lung Cancer ◽

Dna Damage ◽

Small Cell Lung Cancer ◽

Cell Lines ◽

Small Molecule ◽

Cell Lung Cancer ◽

Small Cell ◽

Nsclc Cell ◽

Molecular Compound ◽

Small Cell Lung

AbstractApurinic/apyrimidinic endonuclease 1 (APE1) plays a critical role in the base excision repair (BER) pathway, which is responsible for the excision of apurinic sites (AP sites). In non-small cell lung cancer (NSCLC), APE1 is highly expressed and associated with poor patient prognosis. The suppression of APE1 could lead to the accumulation of unrepaired DNA damage in cells. Therefore, APE1 is viewed as an important marker of malignant tumors and could serve as a potent target for the development of antitumor drugs. In this study, we performed a high-throughput virtual screening of a small-molecule library using the three-dimensional structure of APE1 protein. Using the AP site cleavage assay and a cell survival assay, we identified a small molecular compound, NO.0449-0145, to act as an APE1 inhibitor. Treatment with NO.0449-0145 induced DNA damage, apoptosis, pyroptosis, and necroptosis in the NSCLC cell lines A549 and NCI-H460. This inhibitor was also able to impede cancer progression in an NCI-H460 mouse model. Moreover, NO.0449-0145 overcame both cisplatin- and erlotinib-resistance in NSCLC cell lines. These findings underscore the importance of APE1 as a therapeutic target in NSCLC and offer a paradigm for the development of small-molecule drugs that target key DNA repair proteins for the treatment of NSCLC and other cancers.

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