¹⁷⁷Lu‐DOTMP induces G2/M cell cycle arrest and apoptosis in MG63 cell line

Abstract

Bone pain is the major manifestation of skeletal metastases. Although various treatment modalities are available for bone pain palliation, use of radiolabeled phosphonates is documented to be more effective. Among radionuclides available for this purpose, lutetium-177 is gaining popularity due to its moderate beta energy, theranostic capability, favorable half-life and convenient production logistics. Lu-DOTMP has shown considerable promise as a metastatic bone pain palliating agent in preliminary evaluations and recent clinical studies. Therefore, an attempt was made to elucidate the possible mechanism of in vitro cell death induced by Lu-DOTMP in MG63 cells. Lu-DOTMP binding studies were carried out in mineralized bone of MG63 cells and around 50% binding was observed. Skeletons of Wistar rats showed 1.78 ± 0.5% IA/g at a 3 h time period which was almost constant up to 7 days. MG63 cells were incubated with 3.7 and 37 MBq of Lu-DOTMP for 48 h prior to perform assays. An increase in the magnitude of cell toxicity and apoptotic DNA fragmentation was observed. Enhancement of G2/M phase cell cycle arrest and apoptosis were documented which were dose-dependent. Thus, Lu-DOTMP induced apoptotic cell death in MG63 cells, which might be one of the primary causes of pain relief in osseous metastases.

Efficacy and safety of 177Lu-DOTMP in palliative treatment of symptomatic skeletal metastases: a prospective study

“…Kumar et al . in cell culture studies found that 177 Lu-DOTMP induces apoptotic death of malignant cells by cell cycle arrest at the G2/M phase and might be one of the causes for palliative effect [12]. The patients treated with 177 Lu-DOTMP in the present study achieved an overall response rate of 77%, similar to that of 89 SrCl 2 [11].…”

“…The follow-up bone scans may show a decrease in tumor size with reduction of osteoblastic lesions, suggesting a possible tumoricidal effect and thereby reducing the mechanical effect on the periosteal pain receptors [8,11]. Kumar et al in cell culture studies found that 177 Lu-DOTMP induces apoptotic death of malignant cells by cell cycle arrest at the G2/M phase and might be one of the causes for palliative effect [12]. The patients treated with 177 Lu-DOTMP in the present study achieved an overall response rate of 77%, similar to that of 89 SrCl 2 [11].…”

ComparativeIn VitroCytotoxicity Studies of177Lu-CHX-A″-DTPA-Trastuzumab and177Lu-CHX-A″-DTPA-F(ab′)2-Trastuzumab in HER2-Positive Cancer Cell Lines

“…45 Kumar et al also demonstrated a dose-dependent apoptosis induction and G2/M arrest with 177 Lu-DOTMP in human osteosarcoma (MG-63) cell lines indicating the apoptosis inducing tendency of 177 Lu. 58 Analysis of the apoptotic data further confirmed that induction of overall cytotoxicity by radiation is inversely proportional to HER2 overexpression. The findings of this study are akin to the observations by other authors that overexpression of HER2 suppresses apoptosis owing to mechanisms that disrupt both the intrinsic and extrinsic apoptotic pathways.…”

DNA Damage by Radiopharmaceuticals and Mechanisms of Cellular Repair

“…Notably, studies have demonstrated that 177 Lu induces apoptotic cell death by activating the apoptotic signaling pathway through the downregulation of anti-apoptotic B-cell lymphoma 2 (bcl-2) family genes in human histiocytic lymphoma [139]. In osteosarcoma cell lines, 177 Lu conjugated to ethylenediamine tetramethylene phosphonic (EDTMP) and 1,4,7,10-tetraazacyclododecane-1,4,7,10tetramethylene phosphonic acid (DOTMP) induces G2/M phase cell cycle arrest [143] and DNA fragmentation-associated apoptotic cell death. This is achieved by downregulating bcl-2 and cleavage of the PARP protein, which serves as a substrate for active caspase-3 during cell death [144].…”