Angana Biswas

Significance: No current therapies prevent recurrence in patients with glioblastoma multiforme (GBM). Extracellular matrix (ECM) remodeling and epithelial mesenchymal transition (EMT) are important processes regulating GBM progression and acquisition of radiation and temozolomide (radio/TMZ) resistance. Fli-1 choreographs ECM remodeling and EMT in GBM via transcriptional regulation of HSPB1. Lumefantrine, an antimalarial drug, inhibits the transcriptional activities of Fli-1 and its downstream targets HSPB1, ECM remodeling, and EMT. Lumefantrine is selectively cytotoxic and promotes apoptosis in GBM and reverses radio/TMZ resistance in GBM. This drug can easily be repurposed for management of GBM. Identification of drugs like lumefantrine from FDA-approved therapeutic agents and uncommon sources provides opportunities to broaden the breadth and versatility of current therapeutic regimens for GBM.

Https://doi.org/10.18632/oncotarget.27425 Yetirajam Rajesh, Angana Biswas, Payel Banik, Ipsita Pal, Subhayan Das, Sachin A. Borkar, Hardik Sardana, Abhijit Saha, Swadesh K. Das, Luni Emdad, Paul B....

For the first time we have utilized push–pull stilbene as a visible light activated photoremovable protecting group (PRPG) for the uncaging of alcohols and carboxylic acids. The PRPG efficiently release caged molecules with good photochemical quantum yield. It is capable of monitoring the release in real time owing to its fluorescence “turn on” phenomenon upon photorelease in polar medium. The efficient photorelease and real time monitoring abilities of push–pull stilbene were employed for in vitro drug delivery.

Although there is a strong correlation between multinucleated cells (MNCs) and cancer chemo-resistance in variety of cancers, our understanding of how multinucleated cells modulate the tumor micro-environment is limited. We captured multinucleated cells from triple-negative chemo-resistant breast cancers cells in a time frame, where they do not proliferate but rather significantly regulate their micro-environment. We show that oxidatively stressed MNCs induce chemo-resistance in vitro and in vivo by secreting VEGF and MIF. These factors act through the RAS/MAPK pathway to induce chemo-resistance by upregulating anti-apoptotic proteins. In MNCs, elevated reactive oxygen species (ROS) stabilizes HIF-1α contributing to increase production of VEGF and MIF. Together the data indicate, that the ROS-HIF-1α signaling axis is very crucial in regulation of chemo-resistance by MNCs. Targeting ROS-HIF-1α in future may help to abrogate drug resistance in breast cancer.

Introduction: Glioblastoma multiforme (GBM) accounts for the most aggressive form of tumor showing poor prognosis. Prevailing treatment modality includes chemotherapy with temozolomide (TMZ) concomitant with surgical resection and/or irradiation. However, it has been observed that a number of patients are developing resistance to TMZ owing to its high dosage regimen. The aim of this study is to examine the effects of diosgenin (DSG), a natural steroidal saponin obtained from fenugreek, in combination with TMZ in human GBM cells and TMZ resistant GBM cells. Methodology: The potential of combinatorial chemotherapy for overcoming TMZ resistance was evaluated through development of TMZ resistant GBM clones. These clones were generated by treatment of GBM cells with sub-lethal dose of TMZ over several cycles. Cellular effects were studied by viability assay, flow cytometry and wound healing assay on both single and combined drug treated GBM cells and TMZ resistant cells, respectively. The morphological study and cellular uptake in combined or individual drug treated cells was assessed by microscopy and immunofluorescence staining. The time dependant effect of drugs on invasive and migratory potential of GBM cells and TMZ resistant cells was analysed through zymography for matrix metalloproteinases (MMPs) activity and western blot for apoptotic proteins, epithelial and mesenchymal (EMT) markers, MMPs and VEGF expression. Further, the drug induced apoptosis was also assessed through chromatin condensation and DNA laddering assay. Results: Our investigation shows that co-administration of DSG and TMZ resulted in a substantial increase in GBM cell apoptosis and marked inhibition of cell growth in vitro. Anti-angiogenic and anti-invasive potential of DSG and TMZ were assessed through in vitro studies. At molecular level, DSG and TMZ synergistically lower XIAP expression and cleavage of intracellular death substrates such as PARP thereby shifting the balance from survival to apoptosis as indicated by the rise in the sub-G1 cell population. This combination also alters EMT markers, downregulates the expression of Bcl-xL, Bcl-2, Mcl1, MMPs and VEGF and induces expression of Bax, AIF, cytochrome C. Conclusion: The results suggested that DSG in combination with TMZ reduced the dose of TMZ, when administered singly, and also inhibited the migration and invasion of GBM and TMZ resistant cells. It induced apoptosis and altered the expression of EMT markers. These findings reveal a new therapeutic potential for overcoming TMZ resistance in GBM therapy. This novel modality may be a promising tool for GBM treatment. Citation Format: Y Rajesh, Angana Biswas, Subhayan Das, Mahitosh Mandal. Diosgenin and temozolamide: A potential combinatorial chemotherapy to overcome temozolamide resistance in glioblastoma multiforme [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 4105. doi:10.1158/1538-7445.AM2017-4105