Early results from a phase I study on orally administered tris(8-quinolinolato)gallium(III) (FFC11, KP46) in patients with solid tumors ? a CESAR study (Central European Society for Anticancer Drug Research ? EW

Hofheinz, Ralf; Dittrich, Ch.; Jakupec, Michael A.; Drescher, A.; Jaehde, Ulrich; Gneist, Margit; Keyserlingk, Nikolai Graf v.; Keppler, Bernhard K.; Hochhaus, A

doi:10.5414/cpp43590

Cited by 60 publications

(47 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Currently, the orally bioavailable gallium maltolate and tris(8-quinolinolato)gallium(III) (KP46) are in early clinical development as anticancer agents (7)(8)(9). KP46 was designed to optimize hydrolytic stability and membrane penetration abilities.…”

Section: Introductionmentioning

confidence: 99%

“…Antihypercalcemic as well as antitumor effects were demonstrated in the Walker carcinosarcoma 256 model in rats (11). A first-in-human phase I study revealed favorable tolerability and preliminary evidence of activity against renal cancer (9). Moreover, gallium compounds, including KP46 and gallium nitrate, preferentially accumulate in the bone (12), reflected by the use of radioactive gallium compounds as PET tracers (13).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Calpain-Mediated Integrin Deregulation as a Novel Mode of Action for the Anticancer Gallium Compound KP46

Jungwirth

Gojo

Tuder

et al. 2014

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

On the basis of enhanced tumor accumulation and bone affinity, gallium compounds are under development as anticancer and antimetastatic agents. In this study, we analyzed molecular targets of one of the lead anticancer gallium complexes [KP46, Tris(8-quinolinolato)gallium(III)] focusing on colon and lung cancer. Within a few hours, KP46 treatment at low micromolar concentrations induced cell body contraction and loss of adhesion followed by prompt cell decomposition. This rapid KP46-induced cell death lacked classic apoptotic features and was insensitive toward a pan-caspase inhibitor. Surprisingly, however, it was accompanied by upregulation of proapoptotic Bcl-2 family members. Furthermore, a Bax-but not a p53-knockout HCT-116 subline exhibited significant KP46 resistance. Rapid KP46-induced detachment was accompanied by downregulation of focal adhesion proteins, including several integrin subunits. Loss of integrin-b1 and talin plasma membrane localization corresponded to reduced binding of RGD (Arg-Gly-Asp) peptides to KP46-treated cells. Accordingly, KP46-induced cell death and destabilization of integrins were enhanced by culture on collagen type I, a major integrin ligand. In contrast, KP46-mediated adhesion defects were partially rescued by Mg 2þ ions, promoting integrin-mediated cell adhesion. Focal adhesion dynamics are regulated by calpains via cleavage of multiple cell adhesion molecules. Cotreatment with the cell-permeable calpain inhibitor PD150606 diminished KP46-mediated integrin destabilization and rapid cell death induction. KP46 treatment distinctly inhibited HCT-116 colon cancer xenograft in vivo by causing reduced integrin plasma membrane localization, tissue disintegration, and intense tumor necrosis. This study identifies integrin deregulation via a calpainmediated mechanism as a novel mode of action for the anticancer gallium compound KP46. Mol Cancer Ther; 13(10); 2436-49. Ó2014 AACR.

show abstract

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Calpain-Mediated Integrin Deregulation as a Novel Mode of Action for the Anticancer Gallium Compound KP46

Jungwirth

Gojo

Tuder

et al. 2014

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

show abstract

“…Some of them have shown clinical significance by providing gallium(III) in a more readily available form with positive pharmacokinetic parameters (10,(17)(18)(19).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of the Proteasome Activity by Gallium(III) Complexes Contributes to Their Anti–Prostate Tumor Effects

et al. 2007

View full text Add to dashboard Cite

The investigation of metal-based complexes with potential antitumor activity has been of paramount importance in recent years due to the successful use of cisplatin against various cancers. Gallium(III) and subsequently developed gallium(III)-containing complexes have shown promising antineoplastic effects when tested in a host of malignancies, specifically in lymphomas and bladder cancer. However, the molecular mechanism responsible for their anticancer effect is yet to be fully understood. We report here for the first time that the proteasome is a molecular target for gallium complexes in a variety of prostate cancer cell lines and in human prostate cancer xenografts. We tested five gallium complexes (1-5) in which the gallium ion is bound to an NN ¶O asymmetrical ligand containing pyridine and substituted phenolate moieties in a 1:2 (M/L) ratio. We found that complex 5 showed superior proteasome inhibitory activity against both 26S proteasome (IC 50 , 17 Mmol/L) and purified 20S (IC 50 , 16 Mmol/L) proteasome. Consistently, this effect was associated with apoptosis induction in prostate cancer cells. Additionally, complex 5 was able to exert the same effect in vivo by inhibiting growth of PC-3 xenografts in mice (66%), which was associated with proteasome inhibition and apoptosis induction. Our results strongly suggest that gallium complexes, acting as potent proteasome inhibitors, have a great potential to be developed into novel anticancer drugs.

show abstract

“…[2]. In clinics their cytostatic effects were investigated on humans [6,98]. In this context the first confirmations of the anti-cancer activity of Ga compounds were demonstrated by studying the effects of Ga nitrate, and Ga chloride a.o.…”

Section: +mentioning

confidence: 99%

“…As to Ga quinolinolate (also known as KP46 or FTC11), it was administered to patients with phase I solid tumours and showed a good bioavailability and activity in renal cell carcinoma [98]. Research with gallium protoporphyrin IX (GaP-PIX) was performed initially on bacteria, in mice and since 2004 it has also been used in humans [6].…”

Section: +mentioning

confidence: 99%

Metallomics related to gallium compounds: biochemical and xenobiochemical aspects

Gârban¹,

Silaghi‐Dumitrescu

Gârban³

et al. 2014

Maced. J. Chem. Chem. Eng.

View full text Add to dashboard Cite

Issues concerning chemical compounds studied in the framework of metallomics are of interest both for the domain of biochemistry dealing with the metabolization of nutrients and for xenobiochemistry -a different domain of biochemistry dealing with the biodegradation of xenobiotics. In this context, in vivo and in vitro data are reviewed here on inorganic and organo-metallic compounds of gallium (Ga), ranging from cellular and molecular biology to biochemistry and pathobiochemistry and on to pharmacology and its relations to homeostasis and nutrient degradation.Keywords: gallium compounds -biochemistry; xenobiochemistry; biomedical effects; in vivo; in vitro МЕТАЛОМИКА НА ГАЛИУМОВИ СОЕДИНЕНИЈА: БИОХЕМИСКИ И КСЕНОБИОХЕМИСКИ АСПЕКТИ Проблемите поврзани со хемиските соединенија од областа на металомиката се од интерес не само за биохемијата -домен што се занимава со метаболизмот на хранливите состојки, туку и за ксенобиохемијата -дел од биохемијата што се занимава со биодеградацијата на ксено-биотиците. Во овој труд е направен преглед на податоците in vitro и in vivo за неоргански и органски соединенија на галиум, од аспект на клеточна и молекуларна биологија до биохемија и патобиохемија и фармакологија во однос на хомеостазата и разложувањето на хранливите состојки.Клучни зборови: биохемија; ксенобиохимија; биомедицинско дејство; соединенија на галиум in vivo; in vitro

show abstract

Early results from a phase I study on orally administered tris(8-quinolinolato)gallium(III) (FFC11, KP46) in patients with solid tumors ? a CESAR study (Central European Society for Anticancer Drug Research ? EW

Cited by 60 publications

References 0 publications

Calpain-Mediated Integrin Deregulation as a Novel Mode of Action for the Anticancer Gallium Compound KP46

Calpain-Mediated Integrin Deregulation as a Novel Mode of Action for the Anticancer Gallium Compound KP46

Inhibition of the Proteasome Activity by Gallium(III) Complexes Contributes to Their Anti–Prostate Tumor Effects

Metallomics related to gallium compounds: biochemical and xenobiochemical aspects

Contact Info

Product

Resources

About