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Perillyl alcohol-mediated inhibition of lung cancer cell line proliferation: potential mechanisms for its chemotherapeutic effects.
Toxicol Appl Pharmacol 2004; 195(2):232-46TA

Abstract

Perillyl alcohol (POH) is currently being tested in clinical trials as an anticancer agent, though its mechanism of action has not been definitively established. We treated two human lung cancer cell lines, H322 and H838, with POH to determine its antitumor properties. A sulforhodamine B (SRB) cell proliferation assay was used to determine the effects of POH after 1 and 5 days of treatment with 0.25, 0.5, 0.75, 1.0, and 1.5 mM POH. After 1 day of treatment, little difference could be seen between the lowest and highest concentrations of POH. However, after 5 days, both cell lines showed a dose-dependent decrease in cell proliferation that ranged from 15% to 83%. A clonogenic assay confirmed these results-while there was no significant effect of POH after 1 day of exposure, a dose-dependent decrease in colony formation, ranging from 15% to 100%, was seen after 5 days of treatment. Time-lapse video microscopy revealed that apoptotic cells were evident within 24-48 h of treatment with 1.5 mM POH. The appearance of apoptotic cells was preceded by increased caspase-3 activity and cleavage of poly (ADP-ribose) polymerase (PARP) as POH activated caspase-3 activity 3-6-fold. Nuclear staining with 4',6-diamidino-2-phenylindole (DAPI) confirmed the classical characteristics of apoptosis in POH-treated cells. DNA microarray expression analysis was performed following 8 and 24 (H322) or 8 and 48 (H838) h of treatment with 1.5 mM POH. While a large number of genes were up- or downregulated in the two cell lines at various times after POH treatment, the levels of expression of only eight genes were up- or down-related in both cell lines at both of the time points examined. The significance of these genes as potential mediators of POH action is still uncertain, but the limited number of commonly up- or downregulated genes detected by microarray expression analysis suggests that POH may mediate its effects via posttranscriptional mechanisms. Our results suggest that POH may have potential use as an anticancer drug that stimulates or sensitizes lung tumor cells to apoptosis, and this effect may depend on genetic lesions present in tumor cells.

Authors+Show Affiliations

Department of Cancer Biology, Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC 27157-1082, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

14998688

Citation

Xu, Mian, et al. "Perillyl Alcohol-mediated Inhibition of Lung Cancer Cell Line Proliferation: Potential Mechanisms for Its Chemotherapeutic Effects." Toxicology and Applied Pharmacology, vol. 195, no. 2, 2004, pp. 232-46.
Xu M, Floyd HS, Greth SM, et al. Perillyl alcohol-mediated inhibition of lung cancer cell line proliferation: potential mechanisms for its chemotherapeutic effects. Toxicol Appl Pharmacol. 2004;195(2):232-46.
Xu, M., Floyd, H. S., Greth, S. M., Chang, W. C., Lohman, K., Stoyanova, R., ... Miller, M. S. (2004). Perillyl alcohol-mediated inhibition of lung cancer cell line proliferation: potential mechanisms for its chemotherapeutic effects. Toxicology and Applied Pharmacology, 195(2), pp. 232-46.
Xu M, et al. Perillyl Alcohol-mediated Inhibition of Lung Cancer Cell Line Proliferation: Potential Mechanisms for Its Chemotherapeutic Effects. Toxicol Appl Pharmacol. 2004 Mar 1;195(2):232-46. PubMed PMID: 14998688.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Perillyl alcohol-mediated inhibition of lung cancer cell line proliferation: potential mechanisms for its chemotherapeutic effects. AU - Xu,Mian, AU - Floyd,Heather S, AU - Greth,Suzanne M, AU - Chang,Wen-Chi L, AU - Lohman,Kurt, AU - Stoyanova,Radka, AU - Kucera,Gregory L, AU - Kute,Tim E, AU - Willingham,Mark C, AU - Miller,Mark Steven, PY - 2003/07/11/received PY - 2003/11/03/accepted PY - 2004/3/5/pubmed PY - 2004/4/13/medline PY - 2004/3/5/entrez SP - 232 EP - 46 JF - Toxicology and applied pharmacology JO - Toxicol. Appl. Pharmacol. VL - 195 IS - 2 N2 - Perillyl alcohol (POH) is currently being tested in clinical trials as an anticancer agent, though its mechanism of action has not been definitively established. We treated two human lung cancer cell lines, H322 and H838, with POH to determine its antitumor properties. A sulforhodamine B (SRB) cell proliferation assay was used to determine the effects of POH after 1 and 5 days of treatment with 0.25, 0.5, 0.75, 1.0, and 1.5 mM POH. After 1 day of treatment, little difference could be seen between the lowest and highest concentrations of POH. However, after 5 days, both cell lines showed a dose-dependent decrease in cell proliferation that ranged from 15% to 83%. A clonogenic assay confirmed these results-while there was no significant effect of POH after 1 day of exposure, a dose-dependent decrease in colony formation, ranging from 15% to 100%, was seen after 5 days of treatment. Time-lapse video microscopy revealed that apoptotic cells were evident within 24-48 h of treatment with 1.5 mM POH. The appearance of apoptotic cells was preceded by increased caspase-3 activity and cleavage of poly (ADP-ribose) polymerase (PARP) as POH activated caspase-3 activity 3-6-fold. Nuclear staining with 4',6-diamidino-2-phenylindole (DAPI) confirmed the classical characteristics of apoptosis in POH-treated cells. DNA microarray expression analysis was performed following 8 and 24 (H322) or 8 and 48 (H838) h of treatment with 1.5 mM POH. While a large number of genes were up- or downregulated in the two cell lines at various times after POH treatment, the levels of expression of only eight genes were up- or down-related in both cell lines at both of the time points examined. The significance of these genes as potential mediators of POH action is still uncertain, but the limited number of commonly up- or downregulated genes detected by microarray expression analysis suggests that POH may mediate its effects via posttranscriptional mechanisms. Our results suggest that POH may have potential use as an anticancer drug that stimulates or sensitizes lung tumor cells to apoptosis, and this effect may depend on genetic lesions present in tumor cells. SN - 0041-008X UR - https://www.unboundmedicine.com/medline/citation/14998688/Perillyl_alcohol_mediated_inhibition_of_lung_cancer_cell_line_proliferation:_potential_mechanisms_for_its_chemotherapeutic_effects_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0041008X03005489 DB - PRIME DP - Unbound Medicine ER -