Lonidamine Causes Inhibition of Angiogenesis-Related Endothelial Cell Functions

Bufalo, Donatella Del; Trisciuoglio, Daniela; Scarsella, Marco; d’Amati, Giulia; Candiloro, Antonio; Iervolino, Angela; Leonetti, Carlo; Zupi, Gabriella

doi:10.1593/neo.04133

Cited by 29 publications

(18 citation statements)

References 42 publications

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“…Transformed BJ fibroblasts expressing hTERT and SV40 early region (BJ-EHLT) were maintained as previously described (20). Human M14 melanoma, CG5 breast carcinoma, and HT29 colon carcinoma lines were previously described (45)(46)(47). Human non-small cell lung carcinoma and PC3 prostate cancer cells were obtained from ATCC and maintained in RPMI-1640 supplemented with 10% FCS, 2 mM l-glutamine and antibiotics (Invitrogen).…”

Section: Methodsmentioning

confidence: 99%

Telomere damage induced by the G-quadruplex ligand RHPS4 has an antitumor effect

Salvati¹,

Leonetti²,

et al. 2007

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Functional telomeres are required for the replicability of cancer cells. The G-rich strand of telomeric DNA can fold into a 4-stranded structure known as the G-quadruplex (G4), whose stabilization alters telomere function limiting cancer cell growth. Therefore, the G4 ligand RHPS4 may possess antitumor activity. Here, we show that RHPS4 triggers a rapid and potent DNA damage response at telomeres in human transformed fibroblasts and melanoma cells, characterized by the formation of several telomeric foci containing phosphorylated DNA damage response factors γ-H2AX, RAD17, and 53BP1. This was dependent on DNA repair enzyme ATR, correlated with delocalization of the protective telomeric DNA-binding protein POT1, and was antagonized by overexpression of POT1 or TRF2. In mice, RHPS4 exerted its antitumor effect on xenografts of human tumor cells of different histotype by telomere injury and tumor cell apoptosis. Tumor inhibition was accompanied by a strong DNA damage response, and tumors overexpressing POT1 or TRF2 were resistant to RHPS4 treatment. These data provide evidence that RHPS4 is a telomere damage inducer and that telomere disruption selectively triggered in malignant cells results in a high therapeutic index in mice. They also define a functional link between telomere damage and antitumor activity and reveal the key role of telomere-protective factors TRF2 and POT1 in response to this anti-telomere strategy.

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Section: Methodsmentioning

confidence: 99%

Telomere damage induced by the G-quadruplex ligand RHPS4 has an antitumor effect

Salvati¹,

Leonetti²,

et al. 2007

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“…Next, cells were starved for 24 hours in serum-free medium and then incubated in either serum-free or complete medium in the presence or absence of temsirolimus. Cell proliferation was evaluated after 72 hours by a colorimetric assay as described previously (8).…”

Section: Methodsmentioning

confidence: 99%

“…Morphogenesis on Matrigel of endothelial cells was evaluated as reported previously (8). Cells were plated (2 Â 10 5 per well) on polymerized Matrigel (Becton Dickinson, Bedford, MA) in 1 mL serum-free medium containing 50 ng/mL VEGF (R&D Systems) in the presence or absence (positive control) of temsirolimus (50 nmol/L).…”

Section: Cancer Researchmentioning

confidence: 99%

“…An in vivo Matrigel assay was used to evaluate the ability of temsirolimus to modulate neovascularization (8). Matrigel plugs containing heparin alone (negative control), heparin plus VEGF (positive control), or heparin plus VEGF and temsirolimus were injected s.c. into the flank of 8-week-old C57BL/6 mice (eight mice per group, furnished by the Animal Care Unit of the Regina Elena Cancer Institute, Rome, Italy), and hemoglobin (Hb) content was evaluated after 5 days (8).…”

Section: Cancer Researchmentioning

confidence: 99%

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Antiangiogenic Potential of the Mammalian Target of Rapamycin Inhibitor Temsirolimus

Ciuffreda²,

et al. 2006

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Mammalian target of rapamycin (mTOR) is increasingly recognized as a master regulator of fundamental cellular functions, whose deregulation may underlie neoplastic transformation and progression. Hence, mTOR has recently emerged as a promising target for therapeutic anticancer interventions in several human tumors, including breast cancer. Here, we investigated the antiangiogenic potential of temsirolimus (also known as CCI-779), a novel mTOR inhibitor currently in clinical development for the treatment of breast cancer and other solid tumors. Consistent with previous reports, sensitivity to temsirolimus-mediated growth inhibition varied widely among different breast cancer cell lines and was primarily due to inhibition of proliferation with little, if any, effect on apoptosis induction. In the HER-2 geneamplified breast cancer cell line BT474, temsirolimus inhibited vascular endothelial growth factor (VEGF) production in vitro under both normoxic and hypoxic conditions through inhibition of hypoxia-stimulated hypoxia-inducible factor (HIF)-1A expression and transcriptional activation. Interestingly, these effects were also observed in the MDA-MB-231 cell line, independent of its inherent sensitivity to the growthinhibitory effects of temsirolimus. A central role for mTOR (and the critical regulator of cap-dependent protein translation, eIF4E) in the regulation of VEGF production by BT474 cells was further confirmed using a small interfering RNA approach to silence mTOR and eIF4E protein expression. In addition to its effect on HIF-1A-mediated VEGF production, temsirolimus also directly inhibited serum-and/or VEGFdriven endothelial cell proliferation and morphogenesis in vitro and vessel formation in a Matrigel assay in vivo. Overall, these results suggest that antiangiogenic effects may substantially contribute to the antitumor activity observed with temsirolimus in breast cancer. (Cancer Res 2006; 66(11): 5549-54)

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“…Aliquots of drug-treated and control cells were differentially processed according to the analyses to be done. Cell cycle and apoptosis analysis were done with a FACScan flow cytometer as described previously (36,37).…”

Section: Methodsmentioning

confidence: 99%

Trastuzumab Down-Regulates Bcl-2 Expression and Potentiates Apoptosis Induction by Bcl-2/Bcl-XL Bispecific Antisense Oligonucleotides in HER-2 Gene–Amplified Breast Cancer Cells

Milella¹,

Trisciuoglio

Bruno³

et al. 2004

Clinical Cancer Research

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Purpose: To investigate the possible existence of an antiapoptotic cross-talk between HER-2 and antiapoptotic Bcl-2 family members.Experimental Design: Bcl-2 and Bcl-X L expression and apoptosis induction were analyzed in HER-2 gene-amplified (BT474) and nonamplified (ZR 75-1) breast cancer cell lines exposed to trastuzumab, alone or in combination with either Bcl-2/Bcl-X L bispecific antisense oligonucleotides (AS-4625) or the small-molecule Bcl-2 antagonist HA14-1.Results: In addition to HER-2 and epidermal growth factor receptor, trastuzumab down-regulated Bcl-2, but not Bcl-X L , protein, and mRNA expression in BT474 cells. Interestingly, trastuzumab-induced down-regulation of HER-2 and Bcl-2 was also observed in three of five and two of three breast cancer patients undergoing trastuzumab treatment, respectively. Despite Bcl-2 down-regulation, however, trastuzumab only marginally increased the rate of apoptosis (7.3 ؎ 3.5%). We therefore investigated whether a combination of AS-4625 and trastuzumab might increase proapoptotic efficiency. AS-4625 treatment of BT474 cells decreased both Bcl-2 and Bcl-X L expression, resulting in a 21 ؎ 7% net apoptosis induction; the combination of AS-4625 followed by trastuzumab resulted in a significantly stronger induction of apoptosis (37 ؎ 6%, P < 0.01) that was not observed with the reverse treatment sequence (trastuzumab followed by AS-4625). Similar results were obtained with the Bcl-2 antagonist HA14-1; indeed, exposure of BT474 cells to HA14-1 followed by trastuzumab resulted in a striking proapoptotic synergism (combination index ‫؍‬ 0.58 ؎ 0.18), as assessed by isobologram analysis.Conclusions: Altogether our findings suggest that combined targeting of HER-2 and Bcl-2 may represent a novel, rational approach to more effective breast cancer therapy.

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Lonidamine Causes Inhibition of Angiogenesis-Related Endothelial Cell Functions

Cited by 29 publications

References 42 publications

Telomere damage induced by the G-quadruplex ligand RHPS4 has an antitumor effect

Telomere damage induced by the G-quadruplex ligand RHPS4 has an antitumor effect

Antiangiogenic Potential of the Mammalian Target of Rapamycin Inhibitor Temsirolimus

Trastuzumab Down-Regulates Bcl-2 Expression and Potentiates Apoptosis Induction by Bcl-2/Bcl-XL Bispecific Antisense Oligonucleotides in HER-2 Gene–Amplified Breast Cancer Cells

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