Leucinostatin A inhibits prostate cancer growth through reduction of insulin‐like growth factor‐I expression in prostate stromal cells

Abstract

Targeting stroma in tumor tissues is an attractive new strategy for cancer treatment. We developed in vitro coculture system, in which the growth of human prostate cancer DU-145 cells is stimulated by prostate stromal cells (PrSC) through insulin-like growth factor I (IGF-I). Using this system, we have been searching for small molecules that inhibit tumor growth through modulation of tumor-stromal cell interactions. As a result, we have found that leucinostatins and atpenins, natural antifungal antibiotics, inhibit the growth of DU-145 cells cocultured with PrSC more strongly than that of DU-145 cells alone. In this study we examined the antitumor effects of these small molecules in vitro and in vivo. Growing evidence indicates that the stroma plays a critical role in the growth and metastasis of various cancers, including colorectal, 1 breast, 2,3 pancreatic 4 and prostate cancer.

NBRI16716A, a new antitumor compound against human prostate cancer cells, produced by Perisporiopsis melioloides Mer-f16716

“…8 These compounds were also re-discovered as modulators of tumorstromal cell interactions by our screening program. 5,6 In this paper, we have reported new natural compounds from fungal metabolite.…”

“…Although the study of the precise mechanism is going on, 1 and 2 are considered to modulate the tumor-stromal cell interactions similar to other compounds reported previously. [6][7][8] As we obtained a new compound with potency of antitumor effect in vivo, we thought that our screening concept and program would be beneficial for the innovation of new antitumor drugs. …”

“…6,7 We have recently reported that leucinostatin A, a fungus natural compound, showed antitumor effect against xenograft models of human prostate cancer cells in vivo through the downregulation of insulin-like growth factor-I secretion from PrSCs. 8 By continuing the screening system, we have found new natural compounds from a fungal strain Perisporiopsis melioloides Mer-f16716. In this study we describe the isolation, structure determination and biological activity of NBRI16716A (1), NBRI16716B (2) and NBRI16716C (3).…”

Endophytic Fungi: Novel Sources of Anticancer Molecules

“…Scientists have found that it inhibits prostate cancer growth through the reduction of insulin-like growth factor-I expression in prostate stromal cells (Kawada et al 2010 ). Acremonium sp.…”

Synthesis and Structure–Activity Relationship Study of NBRI16716B, an Antitumor Natural Product

“…Natural products were used as the major source for our screening platform; the structural variety of natural products is expected to bait a diverse array of counterpart proteins. In fact, several natural products exhibit the desired activity and selectivity, including phthoxazolin A, 10) NBRI23477 A and B, 11) leucinostatins, 12) and intervenolin. 13,14) Two of NBRI16716s 15) (Fig.…”