Effect of polyunsaturated fatty acids on the growth of murine colon adenocarcinomas in vitro and in vivo

Summary Polyunsaturated fatty acids (PUFAs) have been implicated in tumour development and have been shown to influence cell proliferation in vitro. We report here that n-3 and n-6 PUFAs at concentration > 10 gM inhibited the proliferation of a human kidney epithelial cell line (2IHKE), which has retained phenotypic characteristics of normal kidney epithelial cells. In contrast, the proliferation was stimulated by n-3 and n-6 PUFAs at concentrations <10 gM under defined growth conditions. The stimulatory effect of n-3 and n-6 PUFAs was even more profound in the presence of EGF. In human kidney epithelial cell lines reflecting different stages of transformation (1IHKE and ITHKEras), the stimulatory effect was abrogated both in the presence and absence of EGF. Saturated fatty acids did not show any stimulatory effect on cell growth. The tyrosine kinase inhibitors genistein and tyrphostin-47 inhibited EGF-induced protein tyrosine phosphorylation dose-dependently in the 2IHKE cells, and abolished the growth stimulatory effect of docosahexaenoic acid (DHA). This indicates the involvement of EGF receptor tyrosine kinase activity in the observed increase in cell proliferation.

Section: Discussionmentioning

confidence: 99%

Differential effect of polyunsaturated fatty acids on cell proliferation during human epithelial in vitro carcinogenesis: involvement of epidermal growth factor receptor tyrosine kinase

Mollerup

Haugen²

1996

“…Brown intracellular vesicles of lipiodol were present in numerous tumour cells, which demonstrated a ballooned, foamy appearance. (Hussey and Tisdale, 1994), and gamma-linoleic acid has been shown to enhance the effect of anticancer treatments (Mudan et al, 1993); linoleic and arachidonic acids are major constituents of lipiodol. Lipiodol is known to localise in human kidney, breast and bladder cancers; further studies are indicated to assess if cellular incorporation of lipiodol occurs in these tumours as well.…”

Section: Resultsmentioning

confidence: 99%

Human liver cancer cells and endothelial cells incorporate iodised oil

Bhattacharya

Dhillon²,

Winslet³

et al. 1996

Summary lodised oil (lipiodol) al., 1985). Lipiodol, an iodinated derivative of poppyseed oil, has been in use for over a decade as a vehicle for targeted cytotoxic or radiotherapeutic treatment of unresectable HCCs. When injected into the hepatic artery the oil is retained by HCCs for several weeks to over a year, but is cleared from normal liver parenchyma within 7 days (Nakakuma et al., 1979). Trials using lipiodol in conjunction with cytotoxic drugs such as doxorubicin, epidoxorubicin, aclarubicin, 5-fluorouracil, mitomycin, cisplatin and SMANCS (a polymer of neocarzinostatin with styrene and maleic acid), or radioisotopes such as 131I have yielded improved survival rates (Bhattacharya et al., 1994). Lipiodol ultra fluid (Laboratoire Guerbet, Roissy Charles de Gaulle, France) is manufactured by ethyl trans-esterification of poppyseed oil, and consists of mono-, di-and tri-iodinated ethyl esters of linoleic (73%), oleic (14%), palmitic (9%) and stearic (3%) acid (I Chastin Laboratoire Guerbet; personal communication) with an iodine content of 37-39% by weight.Hypotheses attempting to explain lipiodol retention in HCCs fall into two major categories. One suggests that lipiodol is retained within the tumour blood vessels, which may be due to an altered electrostatic charge on the endothelial cell surface causing lipid adsorption, or impaired exit of lipid droplets due to altered drainage channels, embolisation being determined by droplet size. The other proposes that lipiodol lodges in the extracellular space, as tumour vessels are more 'leaky' than usual, and because lymphatics are absent in HCCs. Uptake by the reticuloendothelial cells in the liver, spleen, marrow and lungs is the probable route by which lipiodol is cleared when administered systemically, and HCCs may be unable to clear lipiodol because they lack a reticuloendothelial Kupffer cell component. There have been relatively few investigations into the role of the tumour cells (Javitt, 1990). HUVECs were used instead of tumour endothelium. They share a common embryological origin with hepatic sinusoidal endothelium (Hamilton and Mossman, 1976) and also have several surface markers in common with the tumour endothelium in HCCs, namely Ulex Europeus Lectin, Factor VIII and QBendlO (Dhillon et al., 1992). Monolayers of Hep G2 and HUVECs grown on tissue culture chamber slides were exposed for 4, 8, 24 and 32 h to culture media containing 1%, 2% and 4% of lipiodol by volume [in human subjects, bolus injection of 10 ml lipiodol over a period of 1 min into the hepatic artery, which has an average flow of 500 ml min-' (Tygstrup et al., 1962) is likely to yield a lipiodol concentration of 2% in the hepatic arterial blood reaching the tumour]. The iodised oil which is heavier than water, initially remained suspended as fine droplets in the aqueous medium following vigorous agitation and then settled as droplets on the surface of the cell monolayer. Following exposure to lipiodol the monolayers were stained by a silver nitrate impregnation technique adap...

“…Thus, MAC cell lines have been shown to undergo growth stimulation by LA both in vitro and in vivo (Hussey and Tisdale, 1994) and these cell lines show low IC50 values for CV-6504. The oestrogen-independent human breast cancer cell line, MDA-MB-231, is also sensitive to CV-6504.…”

Section: Discussionmentioning

confidence: 99%

“…PUFAs, and LA in particular, have been implicated as tumour promoters (Reddy and Masura, 1984), as enhancers of metastasis and as stimulators of tumour growth in vitro (Wicha et al, 1979) and in vivo (Hussey and Tisdale, 1994). These effects are probably due to metabolism of LA to prostaglandins or products of the lipoxygenase pathways.…”

mentioning

confidence: 99%

Mechanism of the anti-tumour effect of 2,3,5-trimethyl-6-(3-pyridylmethyl) 1,4-benzoquinone (CV-6504)

Hussey

Tisdale²

1997

Self Cite

Summary 2,3,5-Trimethyl-6-(3-pyridylmethyl) 1,4-benzoquinone (CV-6504), an inhibitor of 5-lipoxygenase, effectively suppressed growth of the MAC16 tumour in vivo and prevented the accompanying cachexia, when administered daily at a dose of 10 mg kg-'. There was a reduction in the tumour concentration of linoleic (LA), arachidonic (AA), oleic, stearic and palmitic acid. In order to elucidate the mechanism of the anti-tumour action, the effect of CV-6504 on the metabolism of AA through the 5-, 12-and 15-lipoxygenase pathways has been determined in cell lines sensitive (MAC16, MAC13, MAC26 and Caco-2) and resistant (A549 and DU-145) to CV-6504. Incubation of all cell lines with [3H]AA led to the appearance of [3H]5-, 12-and 1 5-HETE. Preincubation of MAC16, MAC13, MAC26 and Caco-2 with 10 gM CV-6504 inhibited the conversion of AA to 5-, 12-and 15-HETE, while in A549 and DU-145 cells there was no effect on metabolism through any lipoxygenase pathway. Two other cell lines, MDA-MB-231 and PC-3, sensitive to growth inhibition by CV-6504, are known to require LA for growth, while DU-145, which was insensitive to growth inhibition by CV-6504, showed no growth response to LA. These results suggest that some tumours are dependent on lipoxygenase metabolites of LA and AA for their continual growth, and interference with this pathway produces a specific growth inhibition.