| Research Abstract |
Although treatment chemotheutic agents have been used against squamous cell carcinoma, some tumors display resistance to these treatments. As a first step to circumvent the drug-resistance, we examined the sensitivity to carboplatin(CBDCA), derivative of platinum analogue cisplatin, against nine different tumor cell lines established in our laboratory. When these tumor cell lines were cultured with various concentration of CBDCA for 48 h, some cell lines(MIT6, MIT7) were sensitive, while others(MIT8, MIT16) were resistant. Treatment with CBDCA induced decline in mitochondrial membrane potential and caspase-3 activation in the sensitive line MIT7, followed by apoptosis induction. The CBDCA-induced apoptosis was accompanied by post-transcriptional modification ; cleavage of endogenous Bcl-2 and Bcl-xL. In contrast, the two cell lines with CBDCA resistance displayed elevated levels of Bcl-xL expression. The MIT7 overexpressing Bcl-xL showed the resistance to multiple drugs such as CBDCA, mitomycin C, etoposide, and actinomycin D. Furthermore, the combination of Bcl-xL anti-sense oligonucleotide and CBDCA resulted in apotosis of the CBGA-resistant lines MIT8 and MIT16. Together, Bcl-xL was shown to provide multiple drug-resistance. The anti-sense oligonucleotides would be a rational approache to overcome Bcl-xL-mediated multiple-drug resistance.
|
