Centrosome-declustering drugs mediate a two-pronged attack on interphase and mitosis in supercentrosomal cancer cells

Abstract

Classical anti-mitotic drugs have failed to translate their preclinical efficacy into clinical response in human trials. Their clinical failure has challenged the notion that tumor cells divide frequently at rates comparable to those of cancer cells in vitro and in xenograft models. Given the preponderance of interphase cells in clinical tumors, we asked whether targeting amplified centrosomes, which cancer cells carefully preserve in a tightly clustered conformation throughout interphase, presents a superior chemotherapeutic strategy that sabotages interphase-specific cellular activities, such as migration. Herein we have utilized supercentrosomal N1E-115 murine neuroblastoma cells as a test-bed to study interphase centrosome declustering induced by putative declustering agents, such as Reduced-9-bromonoscapine (RedBr-Nos), Griseofulvin and PJ-34. We found tight ‘supercentrosomal' clusters in the interphase and mitosis of ~80% of patients' tumor cells with excess centrosomes. RedBr-Nos was the strongest declustering agent with a declustering index of 0.36 and completely dispersed interphase centrosome clusters in N1E-115 cells. Interphase centrosome declustering caused inhibition of neurite formation, impairment of cell polarization and Golgi organization, disrupted cellular protrusions and focal adhesion contacts—factors that are crucial prerequisites for directional migration. Thus our data illustrate an interphase-specific potential anti-migratory role of centrosome-declustering agents in addition to their previously acknowledged ability to induce spindle multipolarity and mitotic catastrophe. Centrosome-declustering agents counter centrosome clustering to inhibit directional cell migration in interphase cells and set up multipolar mitotic catastrophe, suggesting that disbanding the nuclear–centrosome–Golgi axis is a potential anti-metastasis strategy.

Antimitotic activity of DY131 and the estrogen-related receptor beta 2 (ERRβ2) splice variant in breast cancer

“…To avoid apoptosis triggered by centrosome amplification, cancer cells have evolved ways to cluster or group these extra centrosomes together during cell division [86]. These clustering mechanisms also present a therapeutic opportunity, and centrosome declustering drugs have been proposed as alternatives to conventional antimitotic therapies in breast and other cancers [8–11]. Whether DY131 is a centrosome declustering agent or leads to the appearance of multipolar spindles by other means (or both) remains to be determined.…”

“…MDA-MB-231 cells have supernumerary centrosomes and are sensitive to known centrosome declustering agents (e.g. [10, 11]), but only ~35% of a given population of these cells have clustered centrosomes [86]. It should also be noted that many centrosome declustering drugs can also cause centrosome amplification [10].…”

“…An incomplete mitotic block allows slippage into the next G1 phase where, in the presence of apoptotic defects that may prevent elimination of these cells, chromosomal instability can lead to more aggressive tumor behavior. Other approaches include the inhibition of centrosome clustering, a mechanism to complete bipolar division used by cancer cells with centrosomal amplification; small molecules which inhibit this process are being developed as novel antimitotic therapies in breast and other cancers [8–11]. MYC-mediated modulation of pro-apoptotic BH3-only proteins has also recently been implicated in the control of DiM [12].…”

Turning the headlights on novel cancer biomarkers: Inspection of mechanics underlying intratumor heterogeneity

“…Interestingly, HSET appears non-essential in healthy somatic cells (Godinho and Pellman, 2014; Mountain et al, 1999) but plays a vital role in maintaining the delicate balance between spindle pole separating forces and centrosome clustering forces mediated by a host of proteins like ninein, CLASP, Kid, CENP-E, and NuMA (Godinho and Pellman, 2014). In cells containing extra centrosomes, drugs that interfere with clustering mechanisms disrupt that balance and cause multipolar mitotic catastrophe (Pannu et al, 2014). Centrosome declustering drugs thus show great promise in specifically targeting cancer cells with extra centrosomes (Pannu et al, 2014).…”

“…In cells containing extra centrosomes, drugs that interfere with clustering mechanisms disrupt that balance and cause multipolar mitotic catastrophe (Pannu et al, 2014). Centrosome declustering drugs thus show great promise in specifically targeting cancer cells with extra centrosomes (Pannu et al, 2014). By preventing these more adaptable cells from surviving, declustering drugs not only specifically target cancer cells with CA but also likely direct tumor cell populations to be less genetically malleable and prone to developing ITH.…”