Morphological and biochemical modifications of rat germ cell mitochondria induced by new antispermatogenic compounds: Studies in vivo and in vitro

Effects of Lonidamine on Pituitary-Gonadal Axis in Man

“…In the rat, Lonidamine induces vacuolization and retraction of the apical cytoplasm of Sertoli cells within 24 h, with consequent exfoliation of the immature germ cells into the tubular lumen; later on spermatids and spermatocytes show altered mitochondria, vacuolized nuclei, pyknosis, and karyolysis and appearance of many multinucleated germ cells [4], Similar morphological changes have been described in other mammalian species, including rabbit, beagle dog, and monkey. Spermatogonia do not show any ultrastructural al terations [4], It has been reported that Lonidamine affects the "condensed" [17] mitochondria [8,18,19], reducing cell respiration and consequently increasing glycolysis. Lonidamine has been found to have no effect on Sertoli cell respiration [20], although its in fluence on Sertoli cells has been documented; cultured rat Sertoli cells treated with Lonidamine show large lipid bodies and cytoplasmic vacuoles which originate from the swollen endoplasmic reticulum [20], A single oral dose of Lonidamine in the rat decreases testicular and epididymal androgen-binding protein [21], while the serum androgen-binding protein level is increased.…”

Lonidamine, a New Approach to Cancer Therapy

“…It is known that during spermatogenesis the mito chondria of rat germ cells undergo morphological changes [22][23][24][25][26][27], gradually passing from the orthodox to the condensed form [25,27]; the condensed mito chondrion is the morphologic expression of a func tional state, characterized by a high oxidative capacity associated with a pronounced phosphorylation effi cacy [24], Germ cells with condensed mitochondrion are those susceptible to Lonidamine. Moreover, the cytotoxic activity of this drug or its active analogs is preceded by specific changes of germ cell mitochon dria [14,15,20]. Hence, the indication that the con densed mitochondrion is the target for Lonidamine.…”

“…Hence, the indication that the con densed mitochondrion is the target for Lonidamine. Biochemical studies on germ cells have shown that Lonidamine, and its active derivatives, decrease res piration, the respiratory control rate (RCR), and ADP affinity; these effects are accompanied by an increased glycolysis [15,[28][29][30]. Tumor cells, follow ing in vitro treatment with Lonidamine, also show early and specific ultrastructural changes of mitochon dria, accompanied by respiration decrease; unlike what is observed with the germ cells, glycolysis is also inhibited [4, 28 31].…”

Inhibition of Aerobic Glycolysis in Normal and Neoplastic Lymphoid Cells Induced by Lonidamine [1-(2,4-Dichlorobenzyl)-I-H-indazol-3-carboxylic acid]

“…In particular, a comparison has been made between sensitivity to the drug and cell phenotype, as currently defined by the evaluation of lymphoid cell markers. The data presented indicate that Lonidamine can interfere, to various degrees, with lactate produc tion of normal as well as leukemic bone marrow (B) 1 Supported by CNR 'Progello Finalizzato: Conlrollo della Crescita Neoplástica No. 830089096 and 80164696".…”

“…Lonidamine, I-(2-4-dichlorobenzyl)-l-H-indazoI-3-carboxylic acid, a powerful antispermatogenic com pound [1] has been shown to be a selective inhibitor of aerobic glycolysis of murine tumor cells in vitro [2] and to significantly increase the survival of Ehrlich's carcinoma bearing mice [3]. Recently, it has also been reported that Lonidamine is able to inhibit in vitro the aerobic lactate production of human tumors regard less of their histological type [4], The present study has been made with the aim of evaluating whether Lonidamine can also affect in vitro the energy metabolism of normal human and leuke mic cells.…”