Preclinical Evaluation of an Unconventional Ruthenium-gold-based Chemotherapeutic: RANCE-1, in Clear Cell Renal Cell Carcinoma

Overview

Journal Cancer Med

Specialty Oncology

Date 2019 Jun 14

PMID 31192543

Citations 8

Authors

Benelita T Elie

Karen Hubbard

Yuriy Pechenyy

Buddhadev Layek

Swayam Prabha

Maria Contel

Affiliations

Soon will be listed here.

Abstract

Background: There are few effective treatments for patients with advanced clear cell renal cell carcinoma (CCRCC). Recent findings indicate that ruthenium-gold containing compounds exhibit significant antitumor efficacy against CCRCC in vitro affecting cell viability as well as angiogenesis and markers driving those 2 phenomena. However, no in vivo preclinical evaluation of this class of compounds has been reported.

Methods: Following the dose-finding pharmacokinetic determination, NOD.CB17-Prkdc SCID/J mice bearing xenograft CCRCC Caki-1 tumors were treated in an intervention trial for 21 days at 10 mg/kg/72h of RANCE-1. At the end of the trial, tumor samples were analyzed for histopathological and changes in protein expression levels were assessed.

Results: After 21 days of treatment there was no significant change in tumor size in the RANCE-1-treated mice as compared to the starting size (+3.87%) (P = 0.082) while the vehicle treated mice exhibited a significant tumor size increase (+138%) (P < 0.01). There were no signs of pathological complications as a result of treatment. Significant reduction in the expression of VEGF, PDGF, FGF, EGFR, and HGRF, all key to the proliferation of tumor cells and stromal cells serving protumorigenic purposes was observed.

Conclusions: The tumor growth inhibition displayed and favorable pathology profile of RANCE-1 makes it a promising candidate for further evaluation toward clinical use for the treatment of advanced CCRCC.

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References

Rosenberg S . IL-2: the first effective immunotherapy for human cancer. J Immunol. 2014; 192(12):5451-8. PMC: 6293462. DOI: 10.4049/jimmunol.1490019. View

Fernandez-Gallardo J, Elie B, Sadhukha T, Prabha S, Sanau M, Rotenberg S . Heterometallic titanium-gold complexes inhibit renal cancer cells and . Chem Sci. 2016; 6(9):5269-5283. PMC: 4869729. DOI: 10.1039/C5SC01753J. View

Fernandez-Gallardo J, Elie B, Sulzmaier F, Sanau M, Ramos J, Contel M . Organometallic Titanocene-Gold Compounds as Potential Chemotherapeutics in Renal Cancer. Study of their Protein Kinase Inhibitory Properties. Organometallics. 2014; 33(22):6669-6681. PMC: 4245150. DOI: 10.1021/om500965k. View

Thomas J, Kabbinavar F . Metastatic clear cell renal cell carcinoma: A review of current therapies and novel immunotherapies. Crit Rev Oncol Hematol. 2015; 96(3):527-33. DOI: 10.1016/j.critrevonc.2015.07.009. View

Quail D, Olson O, Bhardwaj P, Walsh L, Akkari L, Quick M . Obesity alters the lung myeloid cell landscape to enhance breast cancer metastasis through IL5 and GM-CSF. Nat Cell Biol. 2017; 19(8):974-987. PMC: 6759922. DOI: 10.1038/ncb3578. View

Elie B, Pechenyy Y, Uddin F, Contel M . A heterometallic ruthenium-gold complex displays antiproliferative, antimigratory, and antiangiogenic properties and inhibits metastasis and angiogenesis-associated proteases in renal cancer. J Biol Inorg Chem. 2018; 23(3):399-411. PMC: 6173830. DOI: 10.1007/s00775-018-1546-8. View

Cui Y, Jiao H, Ye Y, Chen C, Wang J, Tang N . FOXC2 promotes colorectal cancer metastasis by directly targeting MET. Oncogene. 2014; 34(33):4379-90. DOI: 10.1038/onc.2014.368. View

Westbrook J, Cairns D, Peng J, Speirs V, Hanby A, Holen I . CAPG and GIPC1: Breast Cancer Biomarkers for Bone Metastasis Development and Treatment. J Natl Cancer Inst. 2016; 108(4). PMC: 4808632. DOI: 10.1093/jnci/djv360. View

Watari A, Takaki K, Higashiyama S, Li Y, Satomi Y, Takao T . Suppression of tumorigenicity, but not anchorage independence, of human cancer cells by new candidate tumor suppressor gene CapG. Oncogene. 2006; 25(56):7373-80. DOI: 10.1038/sj.onc.1209732. View

10.

Monro S, Colon K, Yin H, Roque 3rd J, Konda P, Gujar S . Transition Metal Complexes and Photodynamic Therapy from a Tumor-Centered Approach: Challenges, Opportunities, and Highlights from the Development of TLD1433. Chem Rev. 2018; 119(2):797-828. PMC: 6453754. DOI: 10.1021/acs.chemrev.8b00211. View

11.

Stadler W, Halabi S, Rini B, Ernstoff M, Davila E, Picus J . A phase II study of gemcitabine and capecitabine in metastatic renal cancer: a report of Cancer and Leukemia Group B protocol 90008. Cancer. 2006; 107(6):1273-9. DOI: 10.1002/cncr.22117. View

12.

Gonzalez-Pantoja J, Stern M, Jarzecki A, Royo E, Robles-Escajeda E, Varela-Ramirez A . Titanocene-phosphine derivatives as precursors to cytotoxic heterometallic TiAu2 and TiM (M = Pd, Pt) compounds. Studies of their interactions with DNA. Inorg Chem. 2011; 50(21):11099-110. PMC: 3205237. DOI: 10.1021/ic201647h. View

13.

Evans S, Clift M, Singh N, de Oliveira Mallia J, Burgum M, Wills J . Critical review of the current and future challenges associated with advanced in vitro systems towards the study of nanoparticle (secondary) genotoxicity. Mutagenesis. 2016; 32(1):233-241. PMC: 5180173. DOI: 10.1093/mutage/gew054. View

14.

Cai J, Tian A, Wang Q, Kong P, Du X, Li X . FOXF2 suppresses the FOXC2-mediated epithelial-mesenchymal transition and multidrug resistance of basal-like breast cancer. Cancer Lett. 2015; 367(2):129-37. DOI: 10.1016/j.canlet.2015.07.001. View

15.

Elie B, Fernandez-Gallardo J, Curado N, Cornejo M, Ramos J, Contel M . Bimetallic titanocene-gold phosphane complexes inhibit invasion, metastasis, and angiogenesis-associated signaling molecules in renal cancer. Eur J Med Chem. 2018; 161:310-322. PMC: 6258019. DOI: 10.1016/j.ejmech.2018.10.034. View

16.

Sevenich L, Joyce J . Pericellular proteolysis in cancer. Genes Dev. 2014; 28(21):2331-47. PMC: 4215179. DOI: 10.1101/gad.250647.114. View

17.

Elie B, Hubbard K, Pechenyy Y, Layek B, Prabha S, Contel M . Preclinical evaluation of an unconventional ruthenium-gold-based chemotherapeutic: RANCE-1, in clear cell renal cell carcinoma. Cancer Med. 2019; 8(9):4304-4314. PMC: 6675714. DOI: 10.1002/cam4.2322. View

18.

Olson O, Joyce J . Cysteine cathepsin proteases: regulators of cancer progression and therapeutic response. Nat Rev Cancer. 2015; 15(12):712-29. DOI: 10.1038/nrc4027. View

19.

Bayat Mokhtari R, Homayouni T, Baluch N, Morgatskaya E, Kumar S, Das B . Combination therapy in combating cancer. Oncotarget. 2017; 8(23):38022-38043. PMC: 5514969. DOI: 10.18632/oncotarget.16723. View

20.

. Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature. 2013; 499(7456):43-9. PMC: 3771322. DOI: 10.1038/nature12222. View