Dietary n-3 polyunsaturated fatty acids enhance hormone ablation therapy in androgen-dependent prostate cancer

Abstract

Hormone ablation therapy typically causes regression of prostate cancer and represents an important means of treating this disease, particularly after metastasis. However, hormone therapy inevitably loses its effectiveness as tumors become androgen-independent, and this conversion often leads to death because of subsequent poor responses to other forms of treatment. Because environmental factors, such as diet, have been strongly linked to prostate cancer, we examined the affects of dietary polyunsaturated fatty acids (PUFAs; at 1.5 wt%) on growth of androgen-dependent (CWR22) and androgen-independent (CWR22R) human prostatic cancer xenografts, the acute response of CWR22 tumors to ablation therapy, and their progression to androgen independence. Significant diet-induced changes in tumor n-3 or n-6 PUFA content had no affect on CWR22 or CWR22R tumors growing with or without androgen support, respectively. However, dietary changes that increased tumor eicosapentaenoic acid and linoleic acid content enhanced responses to ablation therapy, measured by cancer cell apoptosis and mitosis. In addition, relapse to androgen-independent growth (measured by renewed increases in tumor volume and serum prostate-specific antigen after ablation) positively correlated with tumor arachidonic acid content. There was no correlation between expression of 15-lipoxygenase isozymes or their products and tumor growth or responses to ablation. In conclusion, dietary n-3 PUFA may enhance the response of prostate cancer to ablation therapy and retard progression to androgen-independent growth by altering tumor PUFA content.

Figure 1

Mean ratio of apoptosis/mitosis (bar graph) and apoptosis and mitosis levels in AD CWR22 xenograft tumors after 14 days on experimental diet with androgen stimulation.

Figure 2

Mean ratio of apoptosis/mitosis (bar graph) and apoptosis and mitosis levels in AID CWR22R xenograft tumors after 14 days on experimental diet without androgen stimulation. Although there was less mitosis in tumors from the EPA group compared to OA fed mice (*P < 0.05) there was no significant difference in tumor growth as indicated by the ratio of apoptosis/mitosis.

Figure 3

Mean apoptosis/mitosis ratios in AD CWR22 xenograft tumors 5 days after androgen ablation (bar graph) and mean for apoptosis and mitosis levels (*Significantly different from OA and AA dietary groups).

Figure 4

Kaplan-Meier curves indicating days to AID relapse growth, determined by increases in tumor volume after the posthormone ablation nadir. y axis = percentage of animals with AD tumors in remission after ablation (ie, no evidence of renewed AID growth). Drop lines indicate where 50% of the tumors in this study had relapsed to AID. AID growth occurred sooner when mice were fed AA (P < 0.05). Inset indicates correlation of PSA levels with measured tumor size (R² = 0.6035).

Figure 5

Ratio of 15-HETE/13-HODE in xenograft tumors (bar graph; n = 3/group) in CWR22 tumors before (with mean values) and 5 days after ablation and in CWR22R tumors (with mean values) growing without androgen stimulation. CWR22 tumors express higher levels of 15-LOX-2 (Figure 6), with more 15-HETE than 13-HODE in tumors from AA fed mice (white bars), whereas CWR22R tumors express higher levels of 15-LOX-1 and contain relatively more of the LA metabolite 13-HODE.

Figure 6

Relative levels of enzyme expression in AD CWR22 tumors, before (lane 1) and 5 days after ablation (lane 2), and in AID CWR22R tumors (lane 3), all from mice fed AA supplemented diets. A: RT-PCR products; B: Western blot.

Figure 7

Relative levels of 15-LOX mRNA in CWR22 tumors that had converted to AID growth in animals maintained on OA, AA, or EPA experimental diets initiated 7 days before hormone ablation.