Organometallic iridium(III) anticancer complexes with new mechanisms of action: NCI-60 screening, mitochondrial targeting, and apoptosis

Platinum complexes related to cisplatin, cis-[PtCl2(NH3)2], are successful anticancer drugs; however, other transition metal complexes offer potential for combating cisplatin resistance, decreasing side effects, and widening the spectrum of activity. Organometallic half-sandwich iridium (IrIII) complexes [Ir(Cpx)(XY)Cl]+/0 (Cpx = biphenyltetramethylcyclopentadienyl and XY = phenanthroline (1), bipyridine (2), or phenylpyridine (3)) all hydrolyze rapidly, forming monofunctional G adducts on DNA with additional intercalation of the phenyl substituents on the Cpx ring. In comparison, highly potent complex 4 (Cpx = phenyltetramethylcyclopentadienyl and XY = N,N-dimethylphenylazopyridine) does not hydrolyze. All show higher potency toward A2780 human ovarian cancer cells compared to cisplatin, with 1, 3, and 4 also demonstrating higher potency in the National Cancer Institute (NCI) NCI-60 cell-line screen. Use of the NCI COMPARE algorithm (which predicts mechanisms of action (MoAs) for emerging anticancer compounds by correlating NCI-60 patterns of sensitivity) shows that the MoA of these IrIII complexes has no correlation to cisplatin (or oxaliplatin), with 3 and 4 emerging as particularly novel compounds. Those findings by COMPARE were experimentally probed by transmission electron microscopy (TEM) of A2780 cells exposed to 1, showing mitochondrial swelling and activation of apoptosis after 24 h. Significant changes in mitochondrial membrane polarization were detected by flow cytometry, and the potency of the complexes was enhanced ca. 5× by co-administration with a low concentration (5 μM) of the γ-glutamyl cysteine synthetase inhibitor L-buthionine sulfoximine (L-BSO). These studies reveal potential polypharmacology of organometallic IrIII complexes, with MoA and cell selectivity governed by structural changes in the chelating ligands

Growth Inhibition of Human Gynecologic and Colon Cancer Cells by Phyllanthus watsonii through Apoptosis Induction

Phyllanthus watsonii Airy Shaw is an endemic plant found in Peninsular Malaysia. Although there are numerous reports on the anti cancer properties of other Phyllanthus species, published information on the cytotoxicity of P. watsonii are very limited. The present study was carried out with bioassay-guided fractionation approach to evaluate the cytotoxicity and apoptosis induction capability of the P. watsonii extracts and fractions on human gynecologic (SKOV-3 and Ca Ski) and colon (HT-29) cancer cells. P. watsonii extracts exhibited strong cytotoxicity on all the cancer cells studied with IC50 values of ≤ 20.0 µg/mL. Hexane extract of P. watsonii was further subjected to bioassay-guided fractionation and yielded 10 fractions (PW-1→PW-10). PW-4→PW-8 portrayed stronger cytotoxic activity and was further subjected to bioassay-guided fractionation and resulted with 8 sub-fractions (PPWH-1→PPWH-8). PPWH-7 possessed greatest cytotoxicity (IC50 values ranged from 0.66 – 0.83 µg/mL) and was selective on the cancer cells studied. LC-MS/MS analysis of PPWH-7 revealed the presence of ellagic acid, geranic acid, glochidone, betulin, phyllanthin and sterol glucoside. Marked morphological changes, ladder-like appearance of DNA and increment in caspase-3 activity indicating apoptosis were clearly observed in both human gynecologic and colon cancer cells treated with P. watsonii especially with PPWH-7. The study also indicated that P. watsonii extracts arrested cell cycle at different growth phases in SKOV-3, Ca Ski and HT-29 cells. Cytotoxic and apoptotic potential of the endemic P. watsonii was investigated for the first time by bioassay-guided approach. These results demonstrated that P. watsonii selectively inhibits the growth of SKOV-3, Ca Ski and HT-29 cells through apoptosis induction and cell cycle modulation. Hence, P. watsonii has the potential to be further exploited for the discovery and development of new anti cancer drugs

Inhibitory effects of semisynthetic flavonoid derivatives on the biochemical markers of tumor promotion in mouse epidermis in vivo

Two sets of flavonoid derivatives were synthesized from condensed tannins (CTs) or catechin, and compared with the procyanidin monomer models, (+)-catechin and (-)-epicatechin, for their abilities to inhibit the biochemical effects of the potent tumor promoter 12-O-tetradecanoyl-phorbol-13-acetate (TPA) in mouse epidermis in vivo. Topical applications of the semisynthetic flavonoids, catechin dialkyl ketals and epicatechin-4-alkylsulphides inhibit TPA-induced ornithine decarboxylase (ODC) activity to a much greater degree than catechin or epicatechin. Moreover, they reduce TPA-stimulated hydroperoxide (HPx) production, a response that cannot be inhibited by catechin or epicatechin. These compounds also inhibit the sequential stimulations of protein and DNA synthesis linked to TPA promotion. The remarkable effectiveness of these synthetic compounds, especially against the ODC marker of skin tumor promotion, suggests that they may be effective anti-tumor promoters. © 1993

LE DÉVELOPPEMENT DE LA GONADE DES FREEMARTINS

International audienc

Preparation and cytotoxic activity of some new rhodomycin derivatives bearing modifications in the sugar moiety

The synthesis and structural determination of a number of new rhodomycin derivatives, modified in the sugar part are described. The cytotoxicity against leukemic L1210 cells of these compounds is reported, along with β-rhodomycinone and two regioisomers of the above compounds, which were isolated during the synthetic procedure

Development of the gubernaculum and processus vaginalis in freemartinism: Further evidence in support of a specific fetal testis hormone governing male-specific gubernacular development

Background: Freemartinism occurs in some speices of ruminants and affects most female bovine fetuses in hterrosexual, multiple pregnancies owing of susion of the chorionic blood circulations soon after implantation. Maldevelopment of the ovaries and Müllerian ducts have been described and recognized as resulting from exposure of their respective primoridia to an excess of anti-Müllerian hormone. The Present study aimed to analyse the prenatal growth the development of the gubernaculum in freemartins to find out its pssible affliction through foetal testis hormones derived from their male co-twin. Methods: Histolgical sections of young and frawings and photographs of further developed freemartins and conrol male and female bovine foeuses were analysed. The specimens had been collected ealier for analsis of the time course of male and female gonadal and gential development and its impairment associated with freemartinism. Results: The gubernaculum of 35–40 day-old male and female fetuses was in the intial stage of development and of similar appearance in all specimens. Gubenacula of 60–70-day-old male fetuss differed from those of females of similar age in various respects: the male gubernaculum size was larger and extensio