Combination of all-trans retinoic acid and taxol regressed glioblastoma T98G xenografts in nude mice

Abstract

Glioblastoma is the most prevalent and highly malignant brain tumor that continues to defy current treatment strategies. This investigation used all-trans retinoic acid (ATRA) and taxol (TXL) as a combination therapy for controlling the growth of human glioblastoma T98G xenografted in athymic nude mice. Histopathological examination revealed that ATRA induced differentiation and combination of ATRA and TXL caused more apoptosis than either treatment alone. Combination therapy decreased expression of telomerase, nuclear factor kappa B (NFkappacapital VE, Cyrillic), and inhibitor-of-apoptosis proteins (IAPs) indicating suppression of survival factors while upregulated Smac/Diablo. Combination therapy also changed expression of Bax and Bcl-2 proteins leading to increased Bax:Bcl-2 ratio, mitochondrial release of cytochrome c and apoptosis-inducing factor (AIF), and activation of caspase-9. Increased activities of calpain and caspase-3 degraded 270 kD alpha-spectrin at the specific sites to generate 145 kD spectrin breakdown product (SBDP) and 120 kD SBDP, respectively. Further, increased activity of caspase-3 cleaved inhibitor-of-caspase-activated DNase (ICAD). In situ double immunofluorescent labelings showed overexpression of calpain, caspase-12, caspase-3, and AIF during apoptosis, suggesting involvement of both caspase-dependent and caspase-independent pathways for apoptosis. Our investigation revealed that treatment of glioblastoma T98G xenografts with the combination of ATRA and TXL induced differentiation and multiple molecular mechanisms for apoptosis.

Combination of paclitaxel- and retinoic acid-incorporated nanoparticles for the treatment of CT-26 colon carcinoma

“…Karmakar et al (2007Karmakar et al ( , 2008 also reported that the ATRA/paclitaxel combination showed a synergistic antitumor effect in U87MG xenografts in nude mice. They reported that ATRA induced differentiation and combination of ATRA and TXL caused more apoptosis than either treatment alone (Karmakar et al, 2007). Soriano et al also reported the synergistic effect of combination of retinoic acid and paclitaxel against non-small cell lung cancer (A549) (Soriano et al, 1999).…”

All-trans retinoic acid inhibits migration, invasion and proliferation, and promotes apoptosis in glioma cells in vitro

“…Various studies have demonstrated that ATRA can induce differentiation and apoptosis (4,5), as well as induce cell growth arrest, in glioma cells (6). Furthermore, a previous study revealed that ATRA may enhance the bystander effect of suicide-gene therapy against medulloblastoma (7), with a number of studies demonstrating that treatment with ATRA in combination with specific chemoimmunotherapeutic agents may significantly enhance its antitumor effect on glioma (8)(9)(10)(11)(12). These results indicate the therapeutic potential of ATRA for patients with glioma.…”

De-repression of CTGF via the miR-17-92 cluster upon differentiation of human glioblastoma spheroid cultures

“…All-trans retinoic acid (ATRA) is a differentiating agent that is effectively used to treat promyelocytic leukemia (Ohno et al, 2003). In gliomas, ATRA was shown to induce differentiation accompanied by increased apoptosis and decreased proliferation of cell lines both in vitro and in xenograft experiments (Karmakar et al, 2007;Das et al, 2008;Lu et al, 2008). Studies in our laboratories have shown that GBIV stem cell-enriched spheroid cultures become less tumorigenic, less invasive, less angiogenic and more sensitive to therapy after treatment with ATRA simultaneously to stem cell growth-factor removal and serum addition (Campos et al, submitted).…”