Curcumin Affects Components of the Chromosomal Passenger Complex and Induces Mitotic Catastrophe in Apoptosis-Resistant Bcr-Abl-Expressing Cells

Abstract

The Bcr-Abl oncoprotein plays a major role in the development and progression of chronic myeloid leukemia and is a determinant of chemotherapy resistance occurring during the blast crisis phase of the disease. The aim of this article was to investigate the possibility of combating the resistance to apoptosis caused by Bcr-Abl by inducing an alternative cell death process. As a model of chronic myeloid leukemia, we employed Bcr-Abl-transfected mouse progenitor 32D cells with low and high Bcr-Abl expression levels corresponding to drug-sensitive and drug-resistant cells, respectively. The drug curcumin (diferuloylmethane), a known potent inducer of cell death in many cancer cells, was investigated for efficacy with Bcr-Abl-expressing cells. Curcumin strongly inhibited cell proliferation and affected cell viability by inducing apoptotic symptoms in all tested cells; however, apoptosis was a relatively late event. G 2 -M cell cycle arrest, together with increased mitotic index and cellular and nuclear morphology resembling those described for mitotic catastrophe, was observed and preceded caspase-3 activation and DNA fragmentation. Mitosis-arrested cells displayed abnormal chromatin organization, multipolar chromosome segregation, aberrant cytokinesis, and multinucleated cellsmorphologic changes typical of mitotic catastrophe. We found that the mitotic cell death symptoms correlated with attenuated expression of survivin, a member of the chromosomal passenger complex, and mislocalization of Aurora B, the partner of survivin in the chromosomal passenger complex. Inhibition of survivin expression with small interfering RNA exhibited similar mitotic disturbances, thus implicating survivin as a major, albeit not the only, target for curcumin action.This study shows that curcumin can overcome the broad resistance to cell death caused by expression of Bcr-Abl and suggests that curcumin may be a promising agent for new combination regimens for drug-resistant chronic myeloid leukemia.

BCR-ABL Hits at Mitosis; Implications for Chromosomal Instability, Aneuploidy and Therapeutic Strategy

“…High expression of Aurora A in leukemia cell lines and freshly isolated leukemia CML cells has been presented by Ochi T et al (Ochi et al, 2009). We also showed that the expression of BCR-ABL leads to the mislocalization of Aurora A in the chromosomal passenger complex (Wolanin et al, 2006). The importance of Aurora A-dependent signaling in CML has been shown in studies indicating that Aurora inhibitors seem to be very effective therapeutics for CML treatment (Gontarewicz et al, 2008), what will be discussed by us later.…”

“…In case of cancers with the defective p53 function, survivin silencing led to reduced mitotic arrest and enhanced polyploidy, what is a very unwanted and dangerous side-effect. Also in our studies, specific depletion of survivin by siRNA approach in CML cells with checkpoints defects, resulted in strong polyploidization and chromosomal instability (Wolanin et al, 2006). However, when we used a natural compound -curcumin, which has been shown as a broadly acting, very potent anticancer agent, we found that it affects the CPC proteins and induces mitotic catastrophe, however without polyploidization.…”

“…Expression of the non-phosphorylable survivin mutant prevented Aurora B activation and corrected spindle microtubule attachment. We also observed that silencing of survivin in CML cells significantly affected CPC function and mitosis as well as proper completion of cytokinesis leading to the formation of giant polyploid cells (Wolanin et al, 2006). PLK1 also regulates the spindle assembly checkpoint (Nezi & Musacchio, 2009) probably by phosphorylation of BubR1 and finally, regulates chromosome segregation, cytokinesis and mitotic exit.…”

Cell death by bortezomib-induced mitotic catastrophe in natural killer lymphoma cells

“…2D, i-iii). To identify if they were associated with mitosis, these bortezomib-treated SNK-6 cells were examined by immunofluorescence with the MPM-2 antibody, which recognizes the mitosis-specific phosphorylated proteins, thus serving as a marker of mitotic cells (22). As expected, bortezomib induced an accumulation of MPM-2-positive cells among the SNK-6 cells with the chromosomes in total disarray.…”

Superoxide anion and proteasomal dysfunction contribute to curcumin-induced paraptosis of malignant breast cancer cells

“…Such observations suggest that curcumin is a pharmacologically safe agent that may be used not only in cancer chemoprevention, but also in cancer therapy, either as a primary therapeutic agent or as an adjuvant to traditional chemotherapy. Although much of the research into the cancer-killing effects of curcumin has focused on its ability to induce apoptosis [2,3,6,7], curcumin has also been reported to induce nonapoptotic cell death through mitotic catastrophe [8,9] or autophagic cell death [10] in several types of cancer cells.…”