Drug-resistant Human Lung Cancer Cell Research Articles

Amphonal, a new polyene aldehyde from a deep-sea-derived Streptomyces amphotericinicus

A new polyene aldehyde, named amphonal (1), and two known (2 and 3) polyketides were isolated from the deep-sea-derived Streptomyces amphotericinicus OUCT16-38 strain. The structure of 1 was determined by extensive MS and NMR spectroscopic analysis. In the cytotoxicity evaluation, compound 2 showed significant growth inhibition against the drug-resistant human lung cancer cell line A549-Taxol with IC50 value of 0.44 μM, which was more potent than the positive control doxorubicin. Meanwhile, 2 showed considerable cytotoxic effect towards H1975, H1299 and HEL cell lines (IC50 = 0.93-4.73 μM) as well.

Delivery of baicalein and paclitaxel using self-assembled nanoparticles: synergistic antitumor effect in vitro and in vivo.

PurposeCombination anticancer therapy is promising to generate synergistic anticancer effects to maximize the treatment effect and overcome multidrug resistance. The aim of the study reported here was to develop multifunctional, dual-ligand, modified, self-assembled nanoparticles (NPs) for the combination delivery of baicalein (BCL) and paclitaxel (PTX) prodrugs.MethodsProdrug of PTX and prodrug of BCL, containing dual-targeted ligands of folate (FA) and hyaluronic acid (HA), were synthesized. Multifunctional self-assembled NPs for combination delivery of PTX prodrug and BCL prodrug (PTX-BCL) were prepared and the synergistic antitumor effect was evaluated in vitro and in vivo. The in vitro transfection efficiency of the novel modified vectors was evaluated in human lung cancer A549 cells and drug-resistant lung cancer A549/PTX cells. The in vivo antitumor efficiency and systemic toxicity of different formulations were further investigated in mice bearing A549/PTX drug-resistant human lung cancer xenografts.ResultsThe size of the PTX-BCL NPs was approximately 90 nm, with a positive zeta potential of +3.3. The PTX-BCL NPs displayed remarkably better antitumor activity over a wide range of drug concentrations, and showed an obvious synergism effect with CI50 values of 0.707 and 0.513, indicating that double-ligand modification and the co-delivery of PTX and BCL prodrugs with self-assembled NPs had remarkable superiority over other formulations.ConclusionThe prepared PTX-BCL NP drug-delivery system was proven efficient by its targeting of drug-resistant human lung cancer cells and delivering of BCL and PTX prodrugs. Enhanced synergistic anticancer effects were achieved by PTX-BCL NPs, and multidrug resistance of PTX was overcome by this promising targeted nanomedicine.

Preferential accumulation of the near infrared heptamethine dye IR-780 in the mitochondria of drug-resistant lung cancer cells

Personalized oncology significantly relies on the development of theranostic agents to integrate cancer therapeutics and diagnostics. Current strategy for development of such multifunctional agents requires multistep chemical conjugation with cancer specific ligands, contrast agents and therapeutic drugs. In this study, we reported a near infrared (NIR) heptamethine indocyanine dye, IR-780, which selectively accumulated in the mitochondria of drug-resistant human lung cancer cells (A549/DR) and significantly inhibited cell growth, self-renewal and migration without the need of any chemical conjugation. IR-780 was also able to induce A549/DR cell apoptosis by disrupting the mitochondrial function. Furthermore, IR-780 dye exhibited remarkable tumoricidal activity and inhibited tumor recurrence in mouse syngeneic Lewis lung carcinoma xenograft model. With the unique properties of targeting, near infrared imaging and inhibitive effect to the drug-resistant cancer cells both in vitro and in vivo, IR-780 may represent a potential theranostic agent for tumor recurrence.

Membrane and DNA Damaging/Protective Effects of Eugenol, Eucalyptol, Terpinen-4-ol and Camphor at Various Concentrations on Parental and Drug Resistant H1299 Cells

Eugenol, eucalyptol, terpinen-4-ol, and camphor, used as flavor agents in cosmetic and food products, have both prooxidant and antioxidant activities. To clarify the mechanisms of their cytotoxic effect and the factors affecting their antioxidant/prooxidant activities, we investigated cell membrane and DNA damage/protective effects induced by eugenol, eucalyptol, terpinen-4-ol, and camphor in parental and drug-resistant human lung cancer cell lines. The parental cells were found approximately 3, 6, and 8 times more sensitive to camphor cytotoxicity than drug-resistant cells at 24, 48, and 72 h respectively. The cytotoxic activity for both cell types was found to be in the order of camphor, eugenol, terpinen-4-ol, and eucalyptol, depending on their concentrations. Malondialdehyde and 8-hydroxy deoxyguanosine levels were also increased as a result of membrane and DNA damage in both cell lines exposed to the highest concentration of these test components. On the other hand, eugenol, eucalyptol, terpinen-4-ol, and camphor protected the cells against H_2O_2-induced cytotoxicity, membrane damage, and DNA damage when the cells were incubated with these test components at lower concentrations (< IC_{50}) before H_2O_2 treatment. These findings suggest that eugenol, eucalyptol, terpinen-4-ol, and camphor exhibit membrane and DNA protective/damaging effects changing in a manner dependent upon concentration, cell type, and time.

A Comparative Study of the Antioxidant/Prooxidant Effects of Carvacrol and Thymol at Various Concentrations on Membrane and DNA of Parental and Drug Resistant H1299 Cells

Carvacrol and thymol, both used as flavor agents in cosmetic and food products, have prooxidant and antioxidant activities. To clarify the mechanisms of their cytotoxicity and the factors affecting their antioxidant/prooxidant activities, we investigated cell membrane and DNA damage induced by carvacrol and thymol in parental and drug-resistant human lung cancer cell lines. After 24 and 48 hour incubation periods, the cytotoxicity of carvacrol (IC50 380 and 244 microM) was found to be higher than that of thymol (IC50 497 and 266 microM) in parental cells. However, thymol showed higher cytotoxic effects in drug resistant H1299 cells for three incubation periods. Also, carvacrol and thymol, at higher concentrations, increased malondealdehyde (MDA) levels causing membrane damage and 8-hydroxy deoxyguanozine (8-OHdG) levels, causing DNA damage to both parental and drug resistant cells. On the other hand, carvacrol and thymol protected the cells against H2O2-induced cytotoxicity, and membrane and DNA damage when the cells were preincubated with these two compounds at lower concentration (< IC50) before H2O2 incubation. These findings suggest that carvacrol and thymol exhibit protective/damaging effects depending on cell resistance, concentration and time.

Drug-resistant human lung cancer cells are more sensitive to selenium cytotoxicity: Effects on thioredoxin reductase and glutathione reductase

The human U-1285 and GLC 4 cell lines, both derived from small cell carcinoma of the lung, are present in doxorubicin-sensitive (U-1285 and GLC 4) and doxorubicin-resistant MRP-expressing (U-1285dox and GLC 4/ADR) variants. These sublines were examined here with respect to their susceptibilities to the toxic effects of selenite and compared to the toxic effects of selenite on the promyelocytic leukemia cell line HL-60 and its doxorubicin-resistant P-glycoprotein expressing variant. The drug-resistant U-1285dox and GLC 4/ADR sublines proved to be 3- and 4-fold, respectively, more sensitive to the cytotoxicity of selenite than the drug-sensitive U-1285 and GLC 4 sublines, whereas no difference was observed between the HL-60 sublines. The presence of doxorubicin at a concentration equal to the ic 10 did not significantly potentiate the toxic effects of selenite. The presence of selenite did not significantly affect the expression of the multi-drug resistant proteins (MRP1, LRP and topoisomerase IIα) in the drug-resistant cells. The activities of thioredoxin reductase (TrxR) were higher (50 and 25%, respectively) in the drug resistant cell sublines U-1285dox and GLC 4/ADR compared to the drug-sensitive parental lines. The activity of glutathione reductase (GR) was essentially the same in the drug-sensitive and -resistant cell lines. Exposure to selenite resulted in a 4-fold increase in both TrxR and GR activities in U-1285 cells, an effect, which was less pronounced in the presence of doxorubicin. Under similar conditions the increase in the TrxR activity in the resistant U-1285dox cell line, was only 30% and the activity of GR was unaltered. Different responses in the activity of the key enzymes in selenium metabolism are one possible mechanism explaining the differential cytotoxicity of selenium in these cells.

Changes of surface antigens in drug-resistant human lung cancer cell lines and their susceptibility to LAK cells: Takahashi K, Kondo K, Saito S, Kamamura Y, Ichimori T, Hino N et al. Second Department of Surgery, School of Medicine, University of Tokushima, Tokushima. Jpn J Lung Cancer 1995;35:35–41

Changes of surface antigens in drug-resistant human lung cancer cell lines and their susceptibility to LAK cells: Takahashi K, Kondo K, Saito S, Kamamura Y, Ichimori T, Hino N et al. Second Department of Surgery, School of Medicine, University of Tokushima, Tokushima. Jpn J Lung Cancer 1995;35:35–41

薬剤耐性肺癌細胞株の膜抗原の変化とＬＡＫ細胞感受性

薬剤耐性肺癌細胞株の膜抗原の変化とＬＡＫ細胞感受性

Radiation sensitivities in various anticancer-drug-resistant human lung cancer cell lines and mechanism of radiation cross-resistance in a cisplatin-resistant cell line.

To determine whether there exists cross-resistance between anticancer drugs and radiation, six drug-resistant human lung cancer cell lines and their parental cell lines were examined for radiosensitivity using a growth-inhibition assay. Only one cisplatin-resistant cell line, PC-9/CDDP, showed cross-resistance to radiation. The other three cisplatin-resistant cell lines (PC-7/CDDP, PC-4/CDDP, and H69/CDDP), an etoposide-resistant cell line (H69/VP) and a camptothecin-resistant cell line (PC-7/CPT) did not show cross-resistance to radiation. To analyze the mechanism of radiation resistance in PC-9/CDDP cells, the formation and repair of radiation-induced DNA single-strand breaks (ssb) and double-strand breaks (dsb) were examined by alkaline elution and neutral elution respectively. Although the formation of DNA ssb and repair of both DNA ssb and DNA dsb were the same for both cell lines, the formation of DNA dsb in PC-9/CDDP cells was significantly less than those in PC-9 cells. Measurement of intracellular glutathione content in all of the cell lines revealed that only PC-9/CDDP cells had a significant increase of glutathione content compared to the parental cells. Buthionine sulfoximine treatment of PC-9/CDDP cells caused an increase of DNA dsb to the same levels as in PC-9 cells after irradiation and caused a complete radiosensitization. These results indicate that cross-resistance to radiation in drug-resistant cells in a rare phenomenon, and increased glutathione content may play a crucial role in the emergence of cross-resistance to radiation in the drug-resistant cells.