Fine structural and biochemical effects of aminoglutethimide and o,p′‐DDD on rat adrenocortical carcinoma 494 and adrenals

Abstract

Rats bearing adrenocortical carcinoma 494 were injected daily for 7, 14, or 21 days with aminoglutethimide (AG) or o,p'-DDD. Reversibility of these steroidogenic inhibitors was determined by injecting other animals for either 14 or 21 days and sacrificing them 14 days later. While the drugs had little effect on body or tumor growth, plasma corticosterone levels were reduced a maximum of 88% in normal and 95% in tumor-bearing rats during AG chemotherapy. These levels were unaltered in normal rats by o,p'-DDD and reduced a maximum of 64% in tumor-bearing animals. Relative adrenal weights generally increased during chemotherapy and then returned to control levels. These changes were mainly due to alterations in the lipid and mitochondrial volume fractions. Lipid increased with both drugs while mitochondria increased with o,p'-DDD and decreased with AG. Cholesterol ester levels paralleled the lipid stereology more closely with AG than o,p'-DDD. With both drugs the most notable changes in tumor fine structure was a decrease in mitochondrial internal membranous vesicles and matrical density. Adrenal mitochondria had the irregular, elongated forms characteristic of tumor-bearing animals and were vacuolated (AG) or had internal rings (o,p'-DDD). The large lipid droplets observed during chemotherapy with both drugs were replaced by numerous small droplets in recovery periods.

Morphofunctional effects of mitotane on mitochondria in human adrenocortical cancer cells

“…Our data demonstrate that increasing concentrations of MTT, in the range of the therapeutic window (14-20 mg/l corresponding to 43.7-62.5 mM MTT), result in cellular toxicity in H295R cells through the disruption of mitochondrial integrity and functions. Early studies have reported qualitative mitochondrial alterations in adrenals of animals treated with MTT (Kaminsky et al 1962, Moore et al 1980, Krüger et al 1984 and in an estrogen-secreting human ACC cell line. Nevertheless, these effects were observed only at doses as high as 168 mM, whereas 80 mM MTT was not effective on either mitochondrial structure or steroid secretion (Fang 1979).…”

“…However, the mechanism underlying the adrenolytic activity of MTT has not yet been elucidated. Some early sporadic studies have reported the qualitative effects of MTT on animal adrenals (Kaminsky et al 1962, Moore et al 1980, Krüger et al 1984 or on the human atypical estrogen-secreting adrenal cancer cell line Fang-8 (Fang 1979). Recently, by evaluating MTT-induced variation of the proteomic profile of the ACC H295R cell line (Stigliano et al 2008), MTT has been suggested to interact with some proteins belonging to the classes of energetic metabolism, stress response, cytoskeletal structure, and tumorigenesis.…”

Molecular and pharmacological evidence for modulation of kinin B1 receptor expression by endogenous glucocorticoids hormones in rats

“…In the present study, in vivo and in vitro pharmacological and molecular data demonstrate that the endogenous glucocorticoids have a critical role in controlling B 1 receptor expression. This assumption derives from the view that suppression of circulating adrenal hormones, either by surgical (ablation of adrenal glands) or pharmacological (mitotane treatment) ( Schulick & Brennan, 1977 ; Moore et al ., 1980 ; Cai et al ., 1995 ), resulted in a marked up‐regulation of B 1 agonist des‐Arg 9 ‐BK‐mediated contraction in portal vein or paw oedema formation. To explore further whether the up‐regulation of B 1 receptor in ADX rats involves the increase of B 1 receptor expression, we employed a RPA and B 1 kinin receptor encoding mRNA was measured in lung tissues of SO and ADX rats.…”