Zoledronic Acid Reduces Bone Loss and Tumor Growth in an Orthotopic Xenograft Model of Osteolytic Oral Squamous Cell Carcinoma

Abstract

Squamous cell carcinoma (SCC) is the most common form of oral cancer. Destruction and invasion of mandibular and maxillary bone frequently occurs and contributes to morbidity and mortality. We hypothesized that the bisphosphonate drug zoledronic acid (ZOL) would inhibit tumor-induced osteolysis and reduce tumor growth and invasion in a murine xenograft model of bone-invasive oral SCC (OSCC) derived from an osteolytic feline OSCC. Luciferase-expressing OSCC cells (SCCF2Luc) were injected into the perimaxillary subgingiva of nude mice, which were then treated with 100 μg/kg ZOL or vehicle. ZOL treatment reduced tumor growth and prevented loss of bone volume and surface area but had no effect on tumor invasion. Effects on bone were associated with reduced osteolysis and increased periosteal new bone formation. ZOL-mediated inhibition of tumor-induced osteolysis was characterized by reduced numbers of tartrate-resistant acid phosphatasepositive osteoclasts at the tumor-bone interface, where it was associated with osteoclast vacuolar degeneration. The ratio of eroded to total bone surface was not affected by treatment, arguing that ZOL-mediated inhibition of osteolysis was independent of effects on osteoclast activation or initiation of bone resorption. In summary, our results establish that ZOL can reduce OSCC-induced osteolysis and may be valuable as an adjuvant therapy in OSCC to preserve mandibular and maxillary bone volume and function.

Potential molecular targets for inhibiting bone invasion by oral squamous cell carcinoma: a review of mechanisms

“…Although little is known as to whether OSCC cells have the ability to resorb bone themselves, it is clear that osteoclasts are much involved in this process [14][15][16]. Osteoclasts differentiate at the bone surface and dissolve mineral components by an extracellular mechanism involving secretion of acid [17,18].…”

Extracellular Ca2+-dependent enhancement of cytocidal potency of zoledronic acid in human oral cancer cells

“…In conclusion, several preclinical studies have shown that NBPs can reduce tumor growth and invasion in murine allo-and xenograft models of bone-invasive oral squamous cell carcinoma (Cui et al, 2005;Martin et al, 2010). However, no information was provided on whether Ca 2 þ release during bone resorption by oral cancer could enhance the antitumor effects of BPs and contribute to their therapeutic activity.…”

“…It has been widely used in bone metastatic cancers to prevent cancer-induced bone diseases (Coleman, 2012). Notably, ZA has been reported to effectively reduce bone loss and tumor growth in a bone-invasive mouse model of OSCC (Cui et al, 2005;Martin et al, 2010). Furthermore, ZA can inhibit the proliferation of OSCC cells in vitro by inducing apoptosis and/or cell cycle arrest (Tamura et al, 2011).…”

Functions of Diverse Myeloid Cells in the Tumor Micro-Environment

“…Treatment with zoledronic acid was associated with a significant reduction of skeletal-related events and, possibly, direct apoptotic effects in tumour cells. (Martin et al, 2010;Morgan et al, ;Zhang et al, 2010) Our group reported that the anti-tumour agent of marine origin, Trabectedin (Yondelis), was unexpectedly found to be highly cytotoxic to mononuclear phagocytes, including TAMs. This cytotoxic effect is remarkably selective, as neutrophils and lymphocytes were not affected.…”