8-Cl-cAMP induces cell cycle-specific apoptosis in human cancer cells.
8-Cl-cyclic adenosine monophosphate (8-Cl-cAMP) has been known to induce growth inhibition and differentiation in a variety of cancer cells by differential modulation of protein kinase A isozymes. To understand the anticancer activity of 8-Cl-cAMP further, we investigated the effect of 8-Cl-cAMP on apoptosis in human cancer cells. Most of the tested human cancer cells exhibited apoptosis upon treatment with 8-Cl-cAMP, albeit with different sensitivity. Among them, SH-SY5Y neuroblastoma cells and HL60 leukemic cells showed the most extensive apoptosis. The effect of 8-Cl-cAMP was not reproduced by other cAMP analogues or cAMP-elevating agents, showing that the effect of 8-Cl-cAMP was not caused by simple activation of protein kinase A (PKA). However, competition experiments showed that the binding of 8-Cl-cAMP to the cAMP receptor was essential for the induction of apoptosis. After the treatment of 8-Cl-cAMP, cells initially accumulated at the S and G2/M phases of the cell cycle and then apoptosis began to occur among the population of cells at the S/G2/M cell cycle phases, indicating that the 8-Cl-cAMP-induced apoptosis is closely related to cell cycle control. In support of this assumption, 8-Cl-cAMP-induced apoptosis was blocked by concomitant treatment with mimosine, which blocks the cell cycle at early S phase. Interestingly, 8-Cl-cAMP did not induce apoptosis in primary cultured normal cells and non-transformed cell lines, showing that 8-Cl-cAMP-induced apoptosis is specific to transformed cells. Taken together, our results show that the induction of apoptosis is one of the mechanisms through which 8-Cl-cAMP exerts anticancer activity.
Kim
S N
SN
School of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul, Republic of Korea.
Ahn
Y H
YH
Kim
S G
SG
Park
S D
SD
Cho-Chung
Y S
YS
Hong
S H
SH
D016475:3T3 Cells; D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000031:analogs & derivatives* / Q000633:toxicity*; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms; D016466:CHO Cells; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology*; D006224:Cricetinae; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D005260:Female; D016195:G2 Phase; D018922:HL-60 Cells; D006367:HeLa Cells; D006801:Humans; D020014:K562 Cells; D051379:Mice; D008938:Mitosis; D009447:Neuroblastoma; D010051:Ovarian Neoplasms; D011953:Receptors, Cyclic AMP / Q000187:drug effects / Q000502:physiology; D016196:S Phase; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D011953:Receptors, Cyclic AMP; D015124:8-Bromo Cyclic Adenosine Monophosphate; C044258:8-chloro-cyclic adenosine monophosphate; D017868:Cyclic AMP-Dependent Protein Kinases