CXCR4 blockade with AMD3100 enhances Taxol chemotherapy to limit ovarian cancer cell growth

Abstract

The standard of care for ovarian cancer includes initial treatment with chemotherapy. Despite initial efficacy, over 70% of patients develop recurrence; thus, there is a need to identify novel approaches that can improve therapeutic outcomes. We evaluated AMD3100 (Plerixafor), an FDA-approved CXCR4 inhibitor, as a potential adjunctive therapy for low-dose Taxol (Paclitaxel) by assessing the impact on in-vitro ovarian cancer cell proliferation. Proliferation was a measure for both human TOV-112D and murine ID8 ovarian cancer cells incubated with AMD3100 and Taxol, either individually or in combination. Impact of treatment was first determined for the simultaneous administration of AMD3100 and Taxol. We next assessed a sequential application of AMD3100 pretreatment, followed by AMD3100, Taxol, or a combination to test for sensitization to Taxol. In addition, we measured the impact of AMD3100 and Taxol, individually and in combination, on colony formation, an in-vitro model assay of tumor growth. Expression data, as measured by flow cytometry, show that both ID8 and TOV-112D cells are positive for CXCR4, CXCR7, and CXCL12. Combination treatment with AMD3100 (≤10 μmol/l) sensitized both ID8 and TOV-112D cells to low concentrations of Taxol (≤5 nmol/l), limiting cell proliferation and colony formation in vitro. Pretreatment with AMD3100 significantly increased the sensitivity of human ovarian cancer to low-dose Taxol or the combination of AMD3100 and Taxol, although this effect was not evident in murine cells. Importantly, for both human and murine cells, incubation with a combination of AMD3100 and Taxol had the largest impact on limiting cell proliferation. AMD3100 in combination with low-dose Taxol offers improved efficacy and the potential of reduced toxicity for the treatment of ovarian cancer.

The emerging roles of macrophages in cancer metastasis and response to chemotherapy

“…The increase of TAMs following chemotherapy is mostly the result of monocyte recruitment from peripheral circulation, and, to a lesser extent, proliferation of tissue‐resident macrophages . An increased expression of chemotactic agents known to recruit macrophages, including CSF1, CXCL12, and CCL2, are often up‐regulated in tumor cells and tumor‐associated stromal cells in response to cytotoxic chemotherapy . It has also been established that hypoxia induces expression of several chemotactic factors, attracting a variety of BMDCs including monocytes, which differentiate into TAMs expressing the tyrosine kinase receptor TIE2 .…”

“…87,104,109,159,179 An increased expression of chemotactic agents known to recruit macrophages, including CSF1, CXCL12, and CCL2, are often up-regulated in tumor cells and tumor-associated stromal cells in response to cytotoxic chemotherapy. 109,162,180,181 It has also been established that hypoxia induces expression of several chemotactic factors, attracting a variety of BMDCs including monocytes, which differentiate into TAMs expressing the tyrosine kinase receptor TIE2. 179 TIE2 + TAMs are closely associated with tumor vasculature and support angiogenesis in an angiopoietin-2-(ANG2)-dependent manner.…”

The CXL12/CXCR4/CXCR7 axis in female reproductive tract disease: Review

“…66 Importantly, another study detected abundant CXCR7 expression in ovarian cancer tissues and cells. 66 Importantly, another study detected abundant CXCR7 expression in ovarian cancer tissues and cells.…”

“…65 They posit that these factors may also act as a chemo-attractants of malignant cells toward the ovaries. 65 Indeed, Reeves et al 66 showed that ovarian cancer cells incubated with a combination treatment of AMD3100 (≤10 μmol/L) and They further showed that blocking the CXCR4 receptor with AMD3100 repressed the migration of tumorigenic cells.…”

“…They further showed that blocking the CXCR4 receptor with AMD3100 repressed the migration of tumorigenic cells. 65 Indeed, Reeves et al 66 showed that ovarian cancer cells incubated with a combination treatment of AMD3100 (≤10 μmol/L) and…”