Apoptosis and cell-cycle arrest in human and murine tumor cells are initiated by isoprenoids.

Diverse classes of phytochemicals initiate biological responses that effectively lower cancer risk. One class of phytochemicals, broadly defined as pure and mixed isoprenoids, encompasses an estimated 22,000 individual components. A representative mixed isoprenoid, gamma-tocotrienol, suppresses the growth of murine B16(F10) melanoma cells, and with greater potency, the growth of human breast adenocarcinoma (MCF-7) and human leukemic (HL-60) cells. beta-Ionone, a pure isoprenoid, suppresses the growth of B16 cells and with greater potency, the growth of MCF-7, HL-60 and human colon adenocarcinoma (Caco-2) cells. Results obtained with diverse cell lines differing in ras and p53 status showed that the isoprenoid-mediated suppression of growth is independent of mutated ras and p53 functions. beta-Ionone suppressed the growth of human colon fibroblasts (CCD-18Co) but only when present at three-fold the concentration required to suppress the growth of Caco-2 cells. The isoprenoids initiated apoptosis and, concomitantly arrested cells in the G1 phase of the cell cycle. Both suppress 3-hydroxy-3-methylglutaryl CoA reductase activity. beta-Ionone and lovastatin interfered with the posttranslational processing of lamin B, an activity essential to assembly of daughter nuclei. This interference, we postulate, renders neosynthesized DNA available to the endonuclease activities leading to apoptotic cell death. Lovastatin-imposed mevalonate starvation suppressed the glycosylation and translocation of growth factor receptors to the cell surface. As a consequence, cells were arrested in the G1 phase of the cell cycle. This rationale may apply to the isoprenoid-mediated G1-phase arrest of tumor cells. The additive and potentially synergistic actions of these isoprenoids in the suppression of tumor cell proliferation and initiation of apoptosis coupled with the mass action of the diverse isoprenoid constituents of plant products may explain, in part, the impact of fruit, vegetable and grain consumption on cancer risk.

[1]  J. Sambrook,et al.  Molecular Cloning: A Laboratory Manual , 2001 .

[2]  P. Darbre,et al.  Tocotrienols inhibit the growth of human breast cancer cells irrespective of estrogen receptor status , 1998, Lipids.

[3]  Y. Pommier,et al.  Lamin B Phosphorylation by Protein Kinase Cα and Proteolysis during Apoptosis in Human Leukemia HL60 Cells* , 1998, The Journal of Biological Chemistry.

[4]  R. D. Simoni,et al.  Farnesol as a regulator of HMG-CoA reductase degradation: characterization and role of farnesyl pyrophosphatase. , 1997, Archives of biochemistry and biophysics.

[5]  O. Larsson,et al.  Mevalonate-regulated mechanisms in cell growth control: role of dolichyl phosphate in expression of the insulin-like growth factor-1 receptor (IGF-1R) in comparison to Ras prenylation and expression of c-myc. , 1997, Glycobiology.

[6]  A. Qureshi,et al.  Isoprenoids suppress the growth of murine B16 melanomas in vitro and in vivo. , 1997, The Journal of nutrition.

[7]  G. Bruscalupi,et al.  Nuclear lamina assembly in the first cell cycle of rat liver regeneration , 1997, Journal of cellular physiology.

[8]  A. Chambers,et al.  Inhibition of proliferation of estrogen receptor-negative MDA-MB-435 and -positive MCF-7 human breast cancer cells by palm oil tocotrienols and tamoxifen, alone and in combination. , 1997, The Journal of nutrition.

[9]  V. Steele,et al.  Chemoprevention of colon carcinogenesis by dietary perillyl alcohol. , 1997, Cancer research.

[10]  A. Gartel,et al.  p21 (WAF1/CIP1) expression is induced in newly nondividing cells in diverse epithelia and during differentiation of the Caco-2 intestinal cell line. , 1996, Experimental cell research.

[11]  K. Ory,et al.  Cell cycle-dependent regulation of nuclear p53 traffic occurs in one subclass of human tumor cells and in untransformed cells. , 1996, Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research.

[12]  H. Nguyen,et al.  Drug-resistant breast cancer cells frequently retain expression of a functional wild-type p53 protein. , 1996, Carcinogenesis.

[13]  C. Elson,et al.  Suppression of mevalonate pathway activities by dietary isoprenoids: protective roles in cancer and cardiovascular disease. , 1995, The Journal of nutrition.

[14]  F. Mollinedo,et al.  Intracellular Alkalinization Suppresses Lovastatin-induced Apoptosis in HL-60 Cells through the Inactivation of a pH-dependent Endonuclease (*) , 1995, The Journal of Biological Chemistry.

[15]  R. Jirtle,et al.  Induction of apoptosis in liver tumors by the monoterpene perillyl alcohol. , 1995, Cancer research.

[16]  L. Cox,et al.  Weaving a pattern from disparate threads: lamin function in nuclear assembly and DNA replication. , 1994, Journal of cell science.

[17]  G V Sherbet,et al.  Induction of 18A2/mts1 gene expression and its effects on metastasis and cell cycle control. , 1994, DNA and cell biology.

[18]  B. Stewart.  Mechanisms of apoptosis: integration of genetic, biochemical, and cellular indicators. , 1994, Journal of the National Cancer Institute.

[19]  P. Edwards,et al.  Identification of farnesol as the non-sterol derivative of mevalonic acid required for the accelerated degradation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase. , 1994, The Journal of biological chemistry.

[20]  A. Qureshi,et al.  Dietary .beta.-ionone suppresses hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase activity , 1994 .

[21]  Z. Darżynkiewicz,et al.  A selective procedure for DNA extraction from apoptotic cells applicable for gel electrophoresis and flow cytometry. , 1994, Analytical biochemistry.

[22]  W. Willett,et al.  Diet and health: what should we eat? , 1994, Science.

[23]  K. Sigler,et al.  Growth inhibition of rat liver epithelial tumor cells by monoterpenes does not involve Ras plasma membrane association. , 1994, Carcinogenesis.

[24]  Z. Darżynkiewicz,et al.  Flow cytometric detection of apoptosis: comparison of the assays of in situ DNA degradation and chromatin changes. , 1994, Cytometry.

[25]  J. Capeau,et al.  Increased protein kinase C alpha expression in human colonic Caco-2 cells after insertion of human Ha-ras or polyoma virus middle T oncogenes. , 1993, Cancer research.

[26]  R. Parker,et al.  Tocotrienols regulate cholesterol production in mammalian cells by post-transcriptional suppression of 3-hydroxy-3-methylglutaryl-coenzyme A reductase. , 1993, The Journal of biological chemistry.

[27]  V. Hearing,et al.  Malignant melanoma: relationship to parameters of differentiation. , 1991, Melanoma research.

[28]  I Nicoletti,et al.  A rapid and simple method for measuring thymocyte apoptosis by propidium iodide staining and flow cytometry. , 1991, Journal of immunological methods.

[29]  F. McKeon.  Nuclear lamin proteins: domains required for nuclear targeting, assembly, and cell-cycle-regulated dynamics. , 1991, Current opinion in cell biology.

[30]  D. Lowy,et al.  Inhibition of cell growth by lovastatin is independent of ras function. , 1991, Cancer research.

[31]  T. Cotter,et al.  Cell death via apoptosis and its relationship to growth, development and differentiation of both tumour and normal cells. , 1990, Anticancer research.

[32]  J. Goldstein,et al.  Regulation of the mevalonate pathway , 1990, Nature.

[33]  K. Komiyama,et al.  Studies on the biological activity of tocotrienols. , 1989, Chemical & pharmaceutical bulletin.

[34]  A. Kandutsch,et al.  Requirement for mevalonate in cycling cells: Quantitative and temporal aspects , 1988, Journal of cellular physiology.

[35]  M. Barbacid,et al.  Independent molecular pathways in initiation and loss of hormone responsiveness of breast carcinomas. , 1988, Science.

[36]  A. Qureshi,et al.  The structure of an inhibitor of cholesterol biosynthesis isolated from barley. , 1986, The Journal of biological chemistry.

[37]  H. Koeffler,et al.  Increased expression of p53 protein in human leukemia cells. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[38]  I. Weinstein,et al.  Effects of mevinolin and mevalonate on cell growth in several transformed cell lines , 1986, Journal of cellular physiology.

[39]  J. Schlessinger,et al.  Expression of ki‐ras oncogene in tumor cell variants exhibiting different metastatic capabilities , 1985, International journal of cancer.

[40]  V. Rotter,et al.  Major deletions in the gene encoding the p53 tumor antigen cause lack of p53 expression in HL-60 cells. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[41]  R. Weinberg,et al.  The HL-60 transforming sequence: A ras oncogene coexisting with altered myc genes in hematopoietic tumors , 1983, Cell.

[42]  P. Casey,et al.  Protein prenylation: molecular mechanisms and functional consequences. , 1996, Annual review of biochemistry.

[43]  C. Elson.  Novel Lipids and Cancer , 1996 .

[44]  C. Elson.  Novel lipids and cancer. Isoprenoids and other phytochemicals. , 1996, Advances in experimental medicine and biology.

[45]  R. Goldman,et al.  The dynamic properties and possible functions of nuclear lamins. , 1995, International review of cytology.

[46]  E. Wynder,et al.  A rationale for dietary intervention in postmenopausal breast cancer patients: an update. , 1993, Nutrition and cancer.

[47]  B. H. Patterson,et al.  Fruit, vegetables, and cancer prevention: a review of the epidemiological evidence. , 1992, Nutrition and cancer.

[48]  J. Cidlowski,et al.  Rapid in vivo effects of glucocorticoids on the integrity of rat lymphocyte genomic deoxyribonucleic acid. , 1986, Endocrinology.