64

Handbook of Functional Lipids

catabolism [136]. Huang and group [137] also hypothesized that the decrease in
liver cholesterol levels by evening primrose oil in rats is attributed to HMG-CoA
reductase activity, the rate-limiting enzyme of cholesterol biosynthesis; however,
this hypothesis is not further confirmed.

3.4.3 T

UMOR

 

AND

 C

ANCER

One of the proposed mechanisms for the action of PUFAs in modulation of can-
cerous and tumorous cell growth is related to lipid oxidation. EFAs, especially
GLA, AA, EPA, and DHA, are capable of inducing apoptotic cell death of tumor
cells [138–142]. A review provided by Das [143] lists the following as the most
relevant metabolic events in tumor cells that have relation to PUFA metabolism:
(1) excess production of PGE

2

 and PGF

2

α

, which have immunosuppressive action;

(2) decrease in free-radical generation coupled with a relative increase in antioxi-
dative capacity; (3) a decrease in the content of PUFAs, which are necessary to
trigger oxidative metabolism in human neutrophils and tumor cells; and (4) an
increase in polyamines.

Impaired lipid oxidation has been observed in tumor cells [144–146]. EFAs are

important structural components of cell membranes, and thus substrates for gener-
ation of lipid oxidation products, which have inhibitory activity on cell proliferation.
Some PGs derived from cis-unsaturated fatty acids including GLA have antineo-
plastic properties [147,148]. Also, it has been noted that tumor cells (e.g., human
macrophage-like cells, line U-937 and promyelocytic leukemia cells, HL-60) do not
constitutively express phospholipase A

2

 (PLA

2

) activity, but do so when induced to

differentiate  in vitro [149,150]. The PLA

2

 catalyzes the rate-limiting step in the

release of cis-unsaturated fatty acids from the cell membrane lipid pool, which form
precursors to various PGs. Therefore, it can be rationalized that the deficiency in
PLA

2

 activity in tumor cells prevents the formation of antineoplastic PGs. Tumor

cells are also deficient in 

∆

6-desaturase enzyme and secrete excess of PGE

2

, which is

immunosuppressive and mutagenic [151–153]. 

GLA, AA, EPA, and DHA can selectively enhance both superoxide anion and

hydrogen peroxide generation and the level of lipid peroxides in the tumor cells,
but not in normal cells [141,154]. The observed high antioxidant activity and reduced
levels of microsomal cytochrome P450 and cytochrome B5 [155,156] and increased
levels of reduced glutathione content [156,157] in tumor cells is still puzzling. It
has also been observed that decreased levels of superoxide dismutase during early
stages of tumorrogenesis continue to remain depressed [158,159]. The reduction in
lipid peroxidation in tumor cells has been attributed to the increased contents of
lipophilic antioxidants in tumors, which is mainly due to 

α

-tocopherol [160]. In

normal cells, when DNA synthesis is at maximum, lipid peroxidation is suppressed
and vice versa; therefore, cells have evolved a mechanism of changing their antioxidant
content to protect the genetic material from free-radical damage [144,155,161].

DeVries and Van Noorden [159] suggest that the reduced lipid peroxidation in

tumor cells may be due to the lack of adequate amounts of specific PUFA substrates
and also to the loss of the lipid oxidation mechanism. The lack of adequate amounts

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