Pharmacological effect of plumbagin in murine and human prostate cancer cell models

According to the International Agency for Research on Cancer (IARC), prostate cancer (PC) is the second most spread tumor worldwide. The disease is characterized by an abnormal cell division rate of the prostate gland, which is functional in men for the control of the urine output and the homeostasis of spermatozoa. However, following the androgen deprivation therapy, that is considered the first line of treatment, PC generally acquires castration-resistant properties, which are correlated with more aggressive features. Moreover, multiple studies and our preliminary results show that hyaluronic acid (HA) accumulation and subsequently fragmentation into low molecular weight fractions (LMW-HA) are crucial in the progression of several cancers and even in PC recent studies demonstrate an alteration in the enzymes involved in HA metabolism. Indeed, recent experiments validated that hyaluronan fragments were responsible of enhanced cellular proliferation in prostate cancer murine cell models. So far, the role of plumbagin, a natural naphthoquinone and a well-known anti-tumor agent, has been investigated in the modulation of HA metabolism. Hence, the primary aim of the thesis project was to study its pharmacological role and assess whether the natural compound could interfere with hyaluronan metabolism in PC. To demonstrate this, different types of cell models were used: metastatic and non-metastatic PC murine cell lines or androgen-dependent and androgen-independent PC human cell models compared with non-tumoral prostate human cell lines. In our context, plumbagin demonstrated the ability to significantly reduce cell viability, alter cell cycles, modulate the expression of genes and proteins linked to HA metabolism. Herein, important results were obtained by evaluating the reduction of phosphorylated-AKT (p-AKT) in human androgen-dependent PC cell line, a CD44 signaling pathway target that is correlated with pro-oncogenic effects. On the other hand, no toxic effects were highlighted in human non-tumoral PC cell line. Taken together, these results demonstrate that plumbagin inhibits cell growth of metastatic murine and androgen-dependent human PC cell models by targeting HA metabolism. Thus, this thesis project could open a perspective for considering the natural compound in potential synergistic association with standard ADT therapies with the aim of reducing side effects and promote therapeutic outcomes.