Anticancer mechanisms of doxorubicin and zoledronic acid in breast cancer tumor growth in bone

Ottewell, Penelope D.; Woodward, Julia K L; Lefley, Diane V.; Evans, Carla A.; Coleman, Robert E.; Holen, Ingunn

doi:10.1158/1535-7163.mct-09-0462

Cited by 78 publications

(61 citation statements)

References 47 publications

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“…PyMT tumour development, thus, closely mimics the development and progression of human disease. In accordance with previous studies [28][29][30]40], we found that administration of clinically relevant doses doxorubicin (2 mg/kg) followed 24 h later by zoledronic acid (100lg/kg) elicited dramatic anti-tumour effects. Mammary tumours from all 12-to 13-week-old PyMT-MMTV animals that had received combination therapy for 6 weeks were histologically similar, and also comparable in size, to tumours dissected from 6-week-old untreated mice, implying that this therapeutic schedule inhibits essential steps in mammary tumour development and progression.…”

Section: Discussionsupporting

confidence: 92%

“…Previous studies have used human breast cancer cells engrafted either subcutaneously or directly into the tibiae of immunocompromised mice, demonstrating clear effects of combination treatment on rapidly proliferating, immortalised cell lines in vivo [28][29][30]40]. To investigate treatment efficacy on spontaneous mammary tumour development in situ we have now studied immunocompetent FVB mice expressing mouse polyomavirus T antigen [31][32][33].…”

Section: Discussionmentioning

confidence: 99%

“…Doxorubicin and zoledronic acid have both been reported to induce anti-angiogenic effects in tumours when administered alone [38,39], and to decrease the formation of new blood vessels in subcutaneously implanted MDA-MB-436 tumours when given in sequence [40]. We therefore examined whether decreased tumour growth following sequential treatment was associated with a reduction in tumour vascularisation in spontaneously occurring PyMT mammary tumours by assessment of the endothelial cell marker CD34 in 15 mice per treatment group.…”

Section: Effects Of Doxorubicin and Zoledronic Acid On Angiogenesis Amentioning

confidence: 99%

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Combination therapy inhibits development and progression of mammary tumours in immunocompetent mice

Ottewell

Brown

Jones

et al. 2011

Breast Cancer Res Treat

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We have determined the effect of combining the chemotherapy agent doxorubicin and the anti-resorptive drug zoledronic acid on the early stages of spontaneous mammary tumour development using the immunocompetent PyMT mouse model that closely mimics human breast cancer development. 6-week-old PyMT mice were treated weekly for 6 weeks with PBS, 2 mg/kg doxorubicin, 100 μg/kg zoledronic acid or doxorubicin followed 24 h later by zoledronic acid (n = 15/group). Untreated, 6-week-old animals were used for comparison of tumour development. Tumour volume, apoptosis and angiogenesis were analysed on H&E, caspase 3, CD31 and CD34 stained histological sections. Proliferation was measured by BrdU incorporation and Ki67 staining and tumour macrophage infiltration assessed by F4/80 immunohistochemistry. Animals treated with doxorubicin followed by zoledronic acid did not develop palpable mammary tumours, whereas in all other treatment groups tumours progressed to late stage adenocarcinomas. Tumours from the combination treatment group were of comparable size to those in 6-week-old untreated animals, remaining pre-malignant with well-differentiated acinar arrangements and with tumour volume only reaching on average 26% of that in the PBS control group. Tumour cell apoptosis and proliferation was significantly reduced compared to control, single agent or untreated 6-week-old mice. Significantly fewer circulating tumour cells were present in animals following sequential treatment compared to all other groups. Combination treatment with doxorubicin followed by zoledronic acid inhibits development and progression of spontaneously occurring mammary tumours.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Effects Of Doxorubicin and Zoledronic Acid On Angiogenesis Amentioning

confidence: 99%

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Combination therapy inhibits development and progression of mammary tumours in immunocompetent mice

Ottewell

Brown

Jones

et al. 2011

Breast Cancer Res Treat

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“…There are also a wealth of preclinical data reporting that ZOL-induced FPP synthase inhibition has both direct and indirect antitumor effects in breast cancer (3). Preclinical studies have shown sequence-dependent synergy between chemotherapy agents and ZOL (4,5) with maximum effects observed when ZOL is administered 24 hours after chemotherapy. Six cycles of weekly treatment with clinically relevant doses of doxorubicin followed 24 hours later by ZOL inhibited subcutaneous tumor growth in an in vivo mouse model of breast cancer soft tissue disease in the absence of tumor-associated bone disease (6).…”

Section: Introductionmentioning

confidence: 99%

Neoadjuvant Chemotherapy with or without Zoledronic Acid in Early Breast Cancer—A Randomized Biomarker Pilot Study

Winter

Wilson

Syddall

et al. 2013

Clinical Cancer Research

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Purpose: To investigate the short-term biologic effects of neoadjuvant chemotherapy þ/À zoledronic acid (ZOL) in invasive breast cancer.Experimental Design: Forty patients were randomized to receive a single 4 mg infusion of ZOL 24 hours after the first cycle of FE 100 C chemotherapy, or chemotherapy alone. Randomization was stratified for tumor stage, ER, HER2, and menopausal status. All patients had repeat breast core biopsy at day 5 (D5) AE day 21 (D21). Effects on apoptotic index, proliferation (Ki67), growth index, surrogate serum markers of angiogenesis (VEGF), and serum reproductive hormones within the TGFb family (activin-A, TGFb1, inhibin-A, and follistatin) were evaluated and compared.Results: Baseline clinicopathologic characteristics were well balanced. Cell growth index (increased apoptosis and reduced proliferation) fell at D5 in both groups but recovered more rapidly with chemotherapy þ ZOL compared with chemotherapy alone by D21 (P ¼ 0.006). At D5, a greater reduction in serum VEGF occurred with chemotherapy þ ZOL compared with chemotherapy: median percentage change À23.8% [interquartile range (IQR): À32.9 to À15.8] versus À8.4% (IQR: À27.3 to þ8.9; P ¼ 0.02), but these effects were lost by D21. Postmenopausal women showed a decrease in follistatin levels from baseline in the chemotherapy þ ZOL group at D5 and D21, compared with chemotherapy alone (P interaction ¼ 0.051).Conclusions: In this pilot study, short-term changes in biomarkers suggest potentially relevant interactions between tumor biology, chemotherapy, modification of the bone microenvironment, and the endocrine status of the host. Larger studies with more frequent dosing of zoledronic acid are needed to assess these complex interactions more thoroughly.

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“…14) Zoledronic acid (ZOL) is one of the most potent drugs owing to its direct and indirect antitumor effects, 15) and it has been effectively used for the treatment of several cancer cell types such as breast and prostate cancers, acute promyelocytic leukemia, including pancreatic cancers. [16][17][18][19][20] Moreover, ZOL was reported to have an augmenting effect when used with other anticancer agents, 21,22) molecular target agents, 23,24) and radiotherapy. 25) Statins have an inhibitory action on 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA), a rate-limiting enzyme in the mevalonate pathway.…”

mentioning

confidence: 99%

Synergistic Antiproliferative Effects of Zoledronic Acid and Fluvastatin on Human Pancreatic Cancer Cell Lines: An <i>in Vitro</i> Study

Elsayed

Kobayashi

Kubota

et al. 2016

Biological & Pharmaceutical Bulletin

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Bisphosphonates and statins are known to have antitumor activities against different types of cancer cell lines. In the present study, we investigated the antiproliferative effects of the combination of zoledronic acid (ZOL), a bisphophosphonate, and fluvastatin (FLU), a statin, in vitro on two types of human pancreatic cancer cell lines, Mia PaCa-2 and Suit-2. The pancreatic cancer cell lines were treated with ZOL and FLU both individually and in combination to evaluate their antiproliferative effects using WST-8 cell proliferation assay. In this study, we demonstrated a potent synergistic antiproliferative effect of both drugs when used in combination in both cell lines. Moreover, we studied the molecular mechanism behind this synergistic effect, which was inhibited by the addition of the mevalonate pathway products, farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP). Furthermore, we aimed to determine the effect of ZOL and FLU combination on RhoA and Ras guanosine 5′-triphosphate (GTP)-proteins. The combination induced a marked accumulation in RhoA and unprenylated Ras. GGPP and FPP reversed the increase in the amount of both proteins. These results indicated that the combination treatment impaired RhoA and Ras signaling pathway by the inhibition of geranylgeranylation and/or farnesylation. This study provides a potentially effective approach for the treatment of pancreatic cancer using a combination treatment of ZOL and FLU.Key words pancreatic cancer; zoledronic acid; fluvastatin; combination treatment; synergistic Pancreatic cancer is known to be the fifth leading cause of cancer-related mortality in Japan and considered to be one of the most aggressive malignancies. 1) Moreover, patients treated with surgical interventions usually develop tumor relapse and/or liver metastasis.2) Gene mutations, including K-ras, CDKN2A (p16), and TRP53, are often associated with pancreatic cancer.3) Previous studies have shown that blocking and/or depriving cells of K-ras may be a promising way to treat pancreatic cancer. 4,5) Although gemcitabine has been considered the standard care treatment for pancreatic cancer, 6) its clinical use remains limited. Therefore, the development of new therapeutic strategies is needed.The third-generation nitrogen bisphosphonates (NBPs) are currently considered a key therapy for the treatment of osteoclast-mediated bone resorption, bone metastasis, and malignant skeletal-related diseases. 7) NBPs have also shown direct antiproliferative and apoptotic effects on solid tumors [8][9][10][11][12] by inhibiting the farnesyl pyrophosphate (FPP) synthase, a key regulatory enzyme in the mevalonate pathways.13) Impairing the prenylation of small guanosine 5′-triphosphate (GTP) proteins such as Ras, Rab, Rho, and Rac by FPP synthase inhibitors may lead to the loss of many cellular processes. 14)Zoledronic acid (ZOL) is one of the most potent drugs owing to its direct and indirect antitumor effects, 15) and it has been effectively used for the treatment of several cancer cell types...

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Anticancer mechanisms of doxorubicin and zoledronic acid in breast cancer tumor growth in bone

Cited by 78 publications

References 47 publications

Combination therapy inhibits development and progression of mammary tumours in immunocompetent mice

Combination therapy inhibits development and progression of mammary tumours in immunocompetent mice

Neoadjuvant Chemotherapy with or without Zoledronic Acid in Early Breast Cancer—A Randomized Biomarker Pilot Study

Synergistic Antiproliferative Effects of Zoledronic Acid and Fluvastatin on Human Pancreatic Cancer Cell Lines: An <i>in Vitro</i> Study

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