N-(4-Hydroxyphenyl) retinamide potentiated paclitaxel for cell cycle arrest and apoptosis in glioblastoma C6 and RG2 cells.
Glioblastoma grows aggressively due to its ability to maintain abnormally high potentials for cell proliferation. The present study examines the synergistic actions of N-(4-hydroxyphenyl) retinamide (4-HPR) and paclitaxel (PTX) to control the growth of rat glioblastoma C6 and RG2 cell lines. 4-HPR induced astrocytic differentiation that was accompanied by increased expression of the tight junction protein e-cadherin and sustained down regulation of Id2 (member of inhibitor of differentiation family), catalytic subunit of rat telomerase reverse transcriptase (rTERT), and proliferating cell nuclear antigen (PCNA). Flow cytometric analysis showed that the microtubule stabilizer PTX caused cell cycle deregulation due to G2/M arrest. This in turn could alter the fate of kinetochore-spindle tube dynamics thereby halting cell cycle progression. An interesting observation was the induction of G1/S arrest by a combination of 4-HPR and PTX, altering the G2/M arrest induced by PTX alone. This was further ratified by the upregulation of tumor suppressor protein retinoblastoma, which repressed the expression of the key signaling moieties to induce G1/S arrest. Collectively, the combination of 4-HPR and PTX diminished the survival factors (e.g., rTERT, PCNA, and Bcl-2) to make glioblastoma cells highly prone to apoptosis with activation of cysteine proteases (e.g., calpain, cathepsins, caspase-8, caspase-3). Hence, the combination of 4-HPR and PTX can be considered as an effective therapeutic strategy for controlling the growth of heterogeneous glioblastoma cell populations.
Janardhanan
Rajiv
R
Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, 6439 Garners Ferry Road, Columbia, SC 29209, USA.
Butler
Jonathan T
JT
Department of Neurosciences, Medical University of South Carolina, 96 Jonathan Lucas Street, P.O. Box 250606, Charleston, SC 29425, USA.
Banik
Naren L
NL
Department of Neurosciences, Medical University of South Carolina, 96 Jonathan Lucas Street, P.O. Box 250606, Charleston, SC 29425, USA.
Ray
Swapan K
SK
Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, 6439 Garners Ferry Road, Columbia, SC 29209, USA. Electronic address: Swapan.Ray@uscmed.sc.edu.
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D001253:Astrocytes / Q000187:drug effects / Q000502:physiology; D015820:Cadherins / Q000378:metabolism; D002154:Calpain / Q000378:metabolism; D002403:Cathepsins / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects*; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D017313:Fenretinide / Q000494:pharmacology / Q000627:therapeutic use*; D015870:Gene Expression; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051797:Inhibitor of Differentiation Protein 2 / Q000378:metabolism; D017239:Paclitaxel / Q000494:pharmacology / Q000627:therapeutic use*; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D051381:Rats; D019098:Telomerase / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism
D015820:Cadherins; C497451:Id2 protein, rat; D051797:Inhibitor of Differentiation Protein 2; D018809:Proliferating Cell Nuclear Antigen; D025521:Tumor Suppressor Proteins; D017313:Fenretinide; D019098:Telomerase; D002403:Cathepsins; D002154:Calpain; D017239:Paclitaxel