Analgesics and
antineoplastic drugs are often used concurrently for
cancer patients. Our previous study reported that gap junctions composed of connexin32 (Cx32) was implicated in the effect of
analgesics on
cisplatin cytotoxicity. However, the effect of
analgesic on the most widely expressed
connexin (Cx),
connexin43 (
Cx43), and whether such effect mediates the influence on chemotherapeutic efficiency remain unknown. By manipulation of
Cx43 expression or gap junction function, we found that there were gap junction-dependent and independent effect of
Cx43 on temozolomide (TMZ) sensitivity in U87
glioblastoma cells. Studies on survival and apoptosis showed widely used
analgesic tramadol significantly reduced TMZ-induced cytotoxicity in control and negative control cells but not shCx43-transfected cells. Proliferation assay demonstrated
tramadol suppressed TMZ-induced cytotoxicity only on high density (with gap junction formation) but not on low density (without gap junction formation).
Tramadol inhibited
dye-coupling through gap junctions between U87 cells.
Tramadol treatment for 72 h did not alter
Cx43 expression, but decreased
Cx43 phosphorylation accompanied with reduced p-ERK and p-JNK. Our results indicated that long-term treatment with
tramadol reduced TMZ cytotoxicity in U87 cells by suppressing Cx43-composed gap junctions, suggesting identification and usage of antinociceptive drugs which do not downregulate
connexin activity should have beneficial therapeutic consequences.