Calcitriol Analogues Decrease Lung Metastasis but Impair Bone Metabolism in Aged Ovariectomized Mice Bearing 4T1 Mammary Gland Tumours.

Andrzej Mazur,Joanna Banach,Artur Anisiewicz,Andrzej Kutner,Joanna Jarosz,Beata Filip-Psurska,Joanna Wietrzyk,Tomasz Piasecki,Diana Papiernik,Agata Pawlik,Jeanette A Maier,Konrad Kowalski,Anna Nasulewicz-Goldeman,Magdalena Maciejewska

doi:10.14336/ad.2018.0921

Abstract

Calcitriol and its analogues are considered drugs supporting the anticancer treatment of breast cancer and preventing the osteoporosis that results from the development of cancer or from chemotherapy or hormone therapy. Following the orthotopic implantation of 4T1 mammary carcinoma cells into aged ovariectomized (OVX) mice, we evaluated the effects of calcitriol and its two analogues, PRI-2191 and PRI-2205, on metastatic spread and bone homeostasis. Calcitriol and its analogues temporarily inhibited the formation of metastases in the lungs. Unexpectedly, only mice treated with calcitriol analogues showed a deterioration of bone-related parameters, such as bone column density, marrow column density and the CaPO4 coefficient. These findings correlated with an increased number of active osteoclasts differentiated from bone marrow-derived macrophages in mice treated with the analogues. Interestingly, in the tumours from mice treated with PRI-2191 and PRI-2205, the expression of Tnfsf11 (RANKL) was increased. On the other hand, osteopontin (OPN) levels in plasma and tumour tissue, as well as TRAC5b levels in tumours, were diminished by calcitriol and its analogues. Despite a similar action of both analogues towards bone metabolism, their impact on vitamin D metabolism differed. In particular, PRI-2191 and calcitriol, not PRI-2205 treatment significantly diminished the levels of both 25(OH)D3 and 24,25(OH)2D3. In conclusion, though there is evident antimetastatic activity in old OVX mice, signs of increased bone metabolism and deterioration of bone mineralization during therapy with calcitriol analogues were observed.

Highlights

Calcitriol and its analogues are considered drugs supporting the anticancer treatment of breast cancer and preventing the osteoporosis that results from the development of cancer or from chemotherapy or hormone therapy
In our recent studies, we have shown that calcitriol and these two low calcaemic analogues, PRI-2191 and PRI-2205, stimulate the lung metastasis of 4T1 mammary gland tumours growing in young mice
We highlight that the same scheme of treatment used in aged OVX mice has different effects on lung metastasis and tumour angiogenesis than those previously shown in young mice (Fig. 7)

Summary

Introduction

Calcitriol and its analogues are considered drugs supporting the anticancer treatment of breast cancer and preventing the osteoporosis that results from the development of cancer or from chemotherapy or hormone therapy. Only mice treated with calcitriol analogues showed a deterioration of bone-related parameters, such as bone column density, marrow column density and the CaPO4 coefficient. Though there is evident antimetastatic activity in old OVX mice, signs of increased bone metabolism and deterioration of bone mineralization during therapy with calcitriol analogues were observed. Tumour responsiveness to therapeutic agents differs in young and old animals [3,4]. Despite this evidence, the overwhelming majority of research focusing. Calcitriol analogs action in aged mice with breast cancer on the antitumour activity of various compounds is carried out on young animals. Cancer itself [9] and the applied therapeutic schemes that reduce oestrogens level (e.g., oophorectomy, chemotherapy, and aromatase inhibitors) enhance bone resorption without a compensatory increase in bone formation [10,11,12,13]

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Results

Conclusion