Abstract
Glioblastoma resists chemotherapy then recurs as a fatal space-occupying lesion. To improve the prognosis, the issues of chemoresistance and tumor size should be addressed. Glioma stem cell (GSC) populations, a heterogeneous power-law coded population in glioblastoma, are believed to be responsible for the recurrence and progressive expansion of tumors. Thus, we propose a therapeutic strategy of reducing the initial size and controlling the regrowth of GSC populations which directly facilitates initial and long-term control of glioblastoma recurrence. In this study, we administered an anti-glioma/GSC drug temozolomide (TMZ) and OTS964, an inhibitor for T-Lak cell originated protein kinase, in combination (T&O), investigating whether together they efficiently and substantially shrink the initial size of power-law coded GSC populations and slow the long-term re-growth of drug-resistant GSC populations. We employed a detailed quantitative approach using clonal glioma sphere (GS) cultures, measuring sphere survivability and changes to growth during the self-renewal. T&O eliminated self-renewing GS clones and suppressed their growth. We also addressed whether T&O reduced the size of self-renewed GS populations. T&O quickly reduced the size of GS populations via efficient elimination of GS clones. The growth of the surviving T&O-resistant GS populations was continuously disturbed, leading to substantial long-term shrinkage of the self-renewed GS populations. Thus, T&O reduced the initial size of GS populations and suppressed their later regrowth. A combination therapy of TMZ and OTS964 would represent a novel therapeutic paradigm with the potential for long-term control of glioblastoma recurrence via immediate and sustained shrinkage of power-law coded heterogeneous GSC populations.
Highlights
Cancer stealthily occurs from initiating cells [1,2,3,4,5] which continuously reproduce and plastically generate diverse cell types, leading to construction of an extensive heterogeneous cell population [5,6,7,8,9,10]
We found that power-law growth was not disrupted by the glioblastoma/Glioma stem cell (GSC) agent “temozolomide (TMZ)” or an inhibitor for T-Lak cell originated protein kinase (TOPK), OTS964, both TMZ and OTS964 affected GSC population growth in different ways [11, 14, 22, 32,33,34,35]
We previously showed that an inhibitor for T-LAK cell originated protein kinase (TOPK), OTS964, reduced the size of glioma stem cell (GSC) populations (GSC population cell numbers) as represented by glioma sphere (GS) populations in two ways; through clone elimination and through disturbing clone growth in a dose dependent manner [14, 32]
Summary
Cancer stealthily occurs from initiating cells [1,2,3,4,5] which continuously reproduce and plastically generate diverse cell types, leading to construction of an extensive heterogeneous cell population [5,6,7,8,9,10]. The initiating cells in glioblastoma, glioma stem cells (GSCs), are believed to be responsible for tumor recurrence after chemoradiotherapy and for progressive expansion of tumor size [4, 5, 14, 19, 23,24,25,26,27,28,29,30]. GSCs should be targeted to control glioblastoma recurrence and tumor size [19, 28, 30, 31], how they should be targeted remains unclear
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