Wild typep53 sensitizes soft tissue sarcoma cells to doxorubicin by down-regulating multidrug resistance-1 expression

Transcriptional Repression of Protein Kinase Cα via Sp1 by Wild Type p53 Is Involved in Inhibition of Multidrug Resistance 1 P-Glycoprotein Phosphorylation

“…Our current study shows that in addition to direct down-regulation of MDR1 P-glycoprotein by wild type p53 (23), another important mechanism by which WT p53 reverts the MDR phenotype and exerts its anticancer activity is that transcriptional repression of PKC␣ by WT p53 leads to decreased phosphorylation of MDR1 P-glycoprotein. This inhibitory effect on PKC␣ and subsequent decreased phosphorylation of P-glycoprotein by WT p53 is consistent with our previous reports that reintroduction of WT p53 sensitizes STS to chemotherapeutic agents and inhibits STS growth in vitro and in vivo (23,45). In summary, we demonstrated here that restoration of WT p53 into human leiomyosarcoma cells containing mut p53 markedly suppresses PKC␣ transcription through the Sp1 binding site located Ϫ244/Ϫ234 in the promoter upstream of transcription start site.…”

Isolated limb perfusion: a novel delivery system for wild-type p53 and fiber-modified oncolytic adenoviruses to extremity sarcoma

“…[27][28][29] Our own investigations utilizing autologous human primary and metastatic sarcoma have demonstrated that clonal expansion of p53-mutated cells in STS confers a distinct metastatic advantage, 30 and we have previously shown that re-expression of wild-type p53 into STS cells harboring a p53 mutation can induce apoptosis, enhance chemosensitivity, inhibit angiogenesis and prolong survival in vitro and in vivo. [15][16][17] Taking these findings into account, it is logical to investigate the role of wild-type p53 as a therapeutic agent in STS, and results from our preclinical sarcoma models are encouraging. For instance, tumor cell transfection with wild-type p53 caused tumor regression in 40% of mice so treated 15 and also restored STS sensitivity to doxorubicin by downregulating the multidrug-resistance protein-1 (MDR1).…”

“…For instance, tumor cell transfection with wild-type p53 caused tumor regression in 40% of mice so treated 15 and also restored STS sensitivity to doxorubicin by downregulating the multidrug-resistance protein-1 (MDR1). 16 Furthermore, ITI of FLAGp53 resulted in significant tumor growth inhibition. 15 Using ILP instead of ITI of the viral construct, we now report a more diffuse pattern of transgene expression suggesting a possibly more efficient delivery system.…”

“…We sought to address the first issue for several reasons. First, p53 is the most frequently detected mutation in STS, and reconstitution of its wildtype function confers a number of well-documented anticancer outcomes such as growth arrest, 14,15 resensitization to chemotherapy, 16 suppression of invasion and attenuation of angiogenesis. 17 Second, we have previously shown that intra-tumoral injection (ITI) of adenoviral delivered wild-type p53 significantly inhibited STS growth in SCID mice.…”

A modified p53 enhances apoptosis in sarcoma cell lines mediated by doxorubicin

“…Mdm2 has also been shown to induce expression of the multidrug resistance 1 (mdr1) gene and its main product Pglycoprotein (P-gp) (Kondo et al, 1996), which has been implicated in chemoresistance in human sarcomas (Chan et al, 1990;Hoffman et al, 1999;Jiminez et al, 1999). Wild-type p53 can sensitise sarcoma cells harbouring p53 mutations to doxorubicin by downregulating MDR-1 and P-gp expression (Zhan et al, 2001).…”