Lycopene has been suggested as a promising nutritional component for the prevention and treatment of PCa [11,15
]. As a result, many men with PCa increase their intake of lycopene through dietary supplements [28
], although there are no large-scale trials to provide evidence-based clinical practice guidelines [29–32
]. In addition, docetaxel has recently become the first-line chemotherapeutic regimen for CRPC patients. Because lycopene is a potent antioxidant, there is a concern whether lycopene could protect tumor cells as well as the healthy cells from oxidative damage generated by docetaxel-based chemotherapy and therefore attenuate the antitumor efficacy of docetaxel [21
]. In this study, our data clearly demonstrate that lycopene supplementation can significantly enhance the antitumor efficacy of docetaxel in the regression of established tumors in a CRPC xenograft model. This result should justify further clinical investigation of potential benefits of lycopene and docetaxel combinations for treatment of CRPC patients.
Several in vitro
cell culture studies [33
] have suggested that androgen-induced increase in reactive oxygen species (ROS) levels in prostate epithelial cells may play a key role in prostate cancer occurrence, recurrence, and progression. Therefore, agents that prevent the production and chronic accumulation of ROS might be useful in the treatment of prostate cancer. Venkateswaran et al. [34,35
] reported that combinations of antioxidants (i.e., lycopene, vitamin E, and selenium) resulted in a significant reduction in both prostate cancer and liver metastasis in the Lady
transgenic mice, although the authors in this article did not examine whether the anti-prostate cancer effects of these antioxidants were due to their antioxidant properties. However, the authors did show that a combination of vitamin E and selenium did not effectively inhibit prostate cancer in the Lady
transgenic mice. Consistently, Limpens et al. [36
] described that a lycopene and vitamin E combination reduced tumor growth and prostate-specific antigen plasma levels in an orthotopic mouse model of human prostate cancer. Taken together, these studies suggested that lycopene is necessary for the inhibitory effect of this combination on prostate cancer and that nonantioxidant mechanisms are also involved in their antineoplastic actions. Because there are concerns about the use of antioxidants during chemotherapy [21
], the ability of lycopene to inhibit cancer growth through nonantioxidant mechanismsmay provide justification for combination therapies involving this agent and cytotoxic drugs like docetaxel.
IGF-IR not only plays a role in prostate carcinogenesis [37,38
] but also is elevated in metastatic PCa and is associated with resistance to androgen withdraw [17,18,39
]. In addition, maintaining IGF-responsiveness enables PCa survival and growth and is partially acquired through androgen-regulated IGF-IR expression [28
]. These results suggest that IGF-IR is a critical target for prevention and treatment of CRPC. Lycopene has been shown to inhibit IGF-I signaling by down-regulation of IGF-I expression and up-regulation of IGF-BPs [13,14,40,41
]. In this study, we showed that lycopene exhibited more potent inhibitory effects on the growth of DU145 cells with higher expression levels of IGF-IR than those PCa cell lines (e.g., LNCaP, 22Rv1, LAPC-4, PC-3) with lower expression levels of IGF-IR. Moreover, transfected LNCaP cells stably expressing high levels of IGF-IR were approximately 400-fold more sensitive to lycopene than parental LNCaP cells (IC50
for lycopene in LNCaP/IGF-IR was 0.08 µM vs
of 36 µM for parental LNCaP cells). Intriguingly, although lycopene has been reported to be accumulated in LNCaP cells to levels that are 4.5 times higher than in DU145 cells [42
], the growth-inhibitory effects of lycopene on DU145 cells is approximately seven times more pronounced than that on LNCaP cells (IC50
for DU145 vs
LNCaP are 5.1 vs
36 µM). This evidence indicates that IGF-IR levels may be more relevant to the growth-inhibitory effect of lycopene on PCa cell lines than cellular concentrations of lycopene. We hypothesized that lycopene existing in extracellular or membrane compartments may also play a role on IGF-IR activation. Our results confirmed that lycopene increased the expression and secretion of IGF-BP3, which sequesters the IGF-IR ligand. We also showed for the first time that lycopene treatment for only 2 hours can inhibit IGF-I-induced IGF-IR phosphorylation in DU145 cells. This result suggests a direct effect of lycopene on IGF-IR activation. We also showed for the first time that lycopene can inhibit IGF-I-induced IGF-IR phosphorylation in DU145 cells. Further studies are in progress to determine whether lycopene can directly bind to IGF-I or IGF-IR and then inhibit IGF-IR kinase activity.
The general mechanism of IGF-IR activation is to enhance survival and protect cells from apoptosis [16
]. In addition, the IGF-IR interacts with, and influences, various signaling molecules such as ER, AR, EGFR, HER-2, and the DNA damage response pathway [16
]. Together, these properties of IGF-IR activation provide mechanisms through which it can cause resistance to multiple anticancer therapies including chemotherapy, radiotherapy, and targeted therapies [16,25
]. Therefore, in general, anticancer therapies targeting the IGF axis are promising approaches for enhancing the efficacy of many conventional cancer therapies, including docetaxel-based chemotherapy [43
]. We show here that the synergistic growth-inhibitory effect of lycopene and docetaxel was only found on those PCa cancer cell lines with higher IGF-IR levels. This result provides a clue that CRPC patients with high levels of IGF-IR activity may be most likely to benefit from combined therapy with lycopene and docetaxel.
Multiple studies have demonstrated that docetaxel causes cell death through mitotic catastrophe as well as through caspase-dependent and -independent effects [44–46
]. Our study showed that lycopene significantly enhanced the apoptotic effect of docetaxel in PCa both in vitro
in cell cultures and in vivo
in a xenograft model. The histologic analysis of tumor tissue sections revealed that the combination of lycopene and docetaxel resulted in a significant increase in the number of tumor cells with abnormal DNA condensation and multinucleation, consistent with mitotic catastrophe. Further study showed that the docetaxel and lycopene combination could synergistically downregulate survivin expression both in vitro
and in vivo
. Survivin is an antiapoptotic protein and plays a role in cell cycle regulation during mitosis [47
]. Survivin inhibition, alone or in combination with the other therapies, has been shown to induce or enhance apoptosis and mitotic catastrophe in tumor cells [47
]. In addition, survivin is regulated by IGFs and is associated with the resistance to castration and progression in PCa [47–49
]. On the basis of evidences described, we can argue that survivin, serving as a critical downstream event for the combined effects of lycopene and docetaxel, may be a useful biomarker for predicting the outcome or response of this combined therapy in clinical studies.
In summary, these data provide a rationale for the clinical investigation of the efficacy and safety profile of lycopene in combination with docetaxel in CRPC patients. In particular, combining lycopene with docetaxel may provide clinical benefit for men with metastatic CRPC, for whom morbidity and mortality remain high despite wide use of docetaxel chemotherapy. The mechanism of this combined therapy seems to involve the IGF-IR/survivin pathway and is mediated by mitotic catastrophe and apoptosis.