Kigamicin D, a novel anticancer agent based on a new anti‐austerity strategy targeting cancer cells' tolerance to nutrient starvation

Abstract

Both tolerance to nutrient starvation and angiogenesis are essential for cancer progression because of the insufficient supply of nutrients to tumor tissue. Since chronic nutrient starvation seldom occurs in normal tissue, cancer's tolerance to nutrient starvation should provide a novel target for cancer therapy. In this study, we propose an anti-austerity strategy to exploit the ability of agents to eliminate cancer cells' tolerance to nutrient starvation. We established a simple screening method for agents that inhibit cancer cell viability preferentially during nutrient starvation, using PANC-1 cell line cultured in nutrient-rich and nutrientdeprived media. ancers always have deformed, deficient vascular and lymphatic systems due to excessive and unregulated tumor cell growth, as well as improper and insufficient angiogenesis. As a result, perfusion within cancers is inadequate, and the cancers contain regions that are transiently and chronically exposed to nutrient starvation. 1) These microenvironmental inadequacies are present from the earliest stage in the development of cancers, and are fully established while the neoplasm is still microscopic in size. 2) Since nutrient starvation occurs in tumor tissue that is >100-200 µm away from a functional blood supply, 3) tumor survival depends, in part, on the ability to recruit new blood microvessels via angiogenic factors. This affords tumor cells the ability to survive and propagate in a hostile environment, 4) and thus increased angiogenesis by a malignancy is related to a poor prognosis. 5,6) Because of this, antiangiogenic therapy was postulated to be the most promising and specific approach to cancer therapy. Already, extensive studies have been conducted in an attempt to prevent tumor angiogenesis.However, Yu et al. recently suggested that tumors may be able to elude the effect of angiogenesis inhibitors, since antiangiogenic therapy targets genetically stable endothelial cells in the tumor vasculature, and genetic alterations that decrease the vascular dependence of tumor cells can influence the response of tumors to this therapy. 7) The well-known observation that hypovascularity is an outstanding characteristic of pancreatic cancers in diagnostic images suggests that pancreatic cancer tissue has a poor blood supply. 8) However, since pancreatic cancers are known to be among the most aggressive malignancies despite their poor blood supply, we proposed that cancer cells' tolerance of insufficient nutrient might be an important determinant of malignancy. 9) Although the mechanism of tolerance has not yet been fully elucidated, the PI-3K-Akt pathway and AMPK have been found to be involved. 10) Because the blood supply of normal tissue is regulated in a sophisticated manner, angiogenesis is seldom activated in normal healthy adult tissues, except in the female reproductive system. 11) The same is true for nutrient starvation. We therefore speculated that if some compound could abolish cancer cells' tolerance of nutrient starvation, it might be capable of be...

Antitumor Effect of Kigamicin D on Mouse Tumor Models

“…Oral administration of kigamicin D was previously described to show a strong antitumor effect in human tumor xenograft models of pancreatic tumors [2]. In this paper we describe that kigamicin D shows the same selective cytotoxicity against normal human cells such as lung fibroblast and prostate stromal cells under nutrient starved condition as against cancer cells.…”

“…In human pancreatic tumor xenograft models, tumors are thought to keep the natural characteristics of pancreatic cancers such as hypovascularity and aggressive malignant behavior despite poor blood supply. Kigamicin D showed strong antitumor effect on human tumor xenograft models of pancreatic tumors such as PANC-1, Capan-1, and MIA Paca-2 in nude or scid mice [2]. Kigamicin D also showed cytotoxicity selective to nutrient starved culture in normal cells such as fibroblasts and human prostate stromal cells as described below.…”

“…Killing activity against PANC-1 cells under a nutrient starved condition was determined by comparing cell survival after 24 hours incubation in nutrient deprived medium (NDM) with cell survival in DMEM -10% FCS culture as previously described [1,2]. NDM was composed of only electrolytes and vitamins found in the composition of DMEM as following: CaCl 2 (2H 2 O), 265 mg/ml; Fe (NO 3 ) 3 (H 2 O), 0.1 mg/liter; KCl, 400 mg/ml; MgSO 4 (7H 2 O), 200 mg/liter; NaCl, 6400 mg/liter; NaHCO 3 , 700 mg/liter; NaHPO 4 , 125 mg/liter; phenol red, 15 mg/liter; 25 mM HEPES buffer pH 7.4; and MEM vitamin solution (Life technologies, Inc., Rockville, MD).…”

“…It has been evidenced that PI3K promotes angiogenesis, and, PI3K inhibitors such as LY294002 and wortmannin have antiangiogenic activity in vivo [5,6]. Kigamicin D was previously described to inhibit PI3K/Akt pathway and shows antiangiogenic activity [2]. These two findings, namely the cells' response to kigamicin D under nutrient starvation and the antiangiogenesis activity of kigamicin D, prompted us to assess the antitumor spectrum of kigamicin D. We studied human tumor xenograft models other than pancreatic tumors and transplantable syngeneic tumor models.…”

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Abstract Kigamicin D is a novel anticancer agent that was identified using a new screening strategy that targets the tolerance of cancer cells to nutrient starvation [1,2]. Oral administration of kigamicin D was previously described to show a strong antitumor effect in human tumor xenograft models of pancreatic tumors [2].

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