Abstract 3136: Unveiling the therapeutic potential of Tanshinone I on telomerase activity and shelterin complex in myeloma
Authors: Kumar Raman , Khan Rehan , Gupta Nidhi , Seth Tulika , Sharma Alpana 
Published: July 2017

Background and Objectives: Multiple myeloma (MM) defines as monoclonal antibody producing abnormal plasma cells inhabiting bone marrow (BM). It involves multiple genetic mutations where different signaling pathways get deregulated hence showing malignant features of myeloma. Increased relative telomerase activity (RTA) and altered levels of shelterin complex molecules (TRF1, TRF2, POT1, RAP1, TIN2, TPP1) along with its associated molecules (TANK-1 & PINX1) are underlying principle behind several malignancies. This maiden attempt aims to study expression levels of these molecules in myeloma and revealing therapeutic potential of TanshinoneI (TanI) alone or in combination with lenalidomide by targeting telomerase activity and shelterin molecules.

Methodology:Newly diagnosed 50 MM patients & 20 controls were recruited for BM aspiration with their consent. RTA, mean telomere length, relative mRNA and protein levels were studied in study subjects. Clinical parameters were recorded; correlation was studied between all the studied genes at mRNA levels and between genes and patients’ clinical parameters; ROC curves were plotted of all genes. Anti cancer potential of TanI and lenalidomide or their combination were studied with different assays on myeloma cells (RPMI8226 & U266).

Results:Significantly (p&lt;0.05) high relative mRNA expression were found of all molecules except PINX1 which was significantly lowered in patients compared to controls and was correlating with disease severity and progression. Similarly, higher RTA and lowered mean telomere length was observed in patients. Statistically significant correlation was observed between genes, telomerase activity and with clinical parameters. ROC curves analysis showed very high sensitivity and specificity for TRF2 genes and Telomerase activity. Thus, RTA and shelterin complex along with associated factors does play role in causing myeloma and its progression. TanI caused significant toxicity at low doses in myeloma cells while lenalidomide did not have any toxicity. Cell death was enhanced when combination of both (TanI + lenalidomide) drugs were used as observed in Annexin-V/PI and Tunel assay. TanI and its combination with lenalidomide significantly down regulated protein expression of TANK1, TPP1, and RAP1 in myeloma cells compared to untreated cells.

Conclusions:In nutshell, study implies that increased RTA along with altered mRNA and protein expression of shelterin complex molecules with its associated partners might play role in pathogenesis and progression of MM. Stage-wise significant increased expression and correlation of these molecules with each other and with clinical parameters showed their role as potential bio-marker in MM. Significant down-regulation of RTA and apoptosis by TanI alone or combination with lenalidomide suggests that TanI might have synergizing effect with lenalidomide in causing cytotoxicity in Myeloma.

Note: This abstract was not presented at the meeting.

Citation Format: Raman Kumar, Rehan Khan, Nidhi Gupta, Tulika Seth, Alpana Sharma. Unveiling the therapeutic potential of Tanshinone I on telomerase activity and shelterin complex in myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3136. doi:10.1158/1538-7445.AM2017-3136