Prion-like Nanofibrils of Small Molecules (PriSM) Selectively Inhibit Cancer Cells by Impeding Cytoskeleton Dynamics

Abstract

Background: Small molecules form prion-like nanofibrils termed as PriSM. Results: PriSM accumulate selectively in cancer cells and impede cytoskeleton dynamics. Conclusion: PriSM is selectively toxic to cancer cells. Significance: We hope this work will inspire the exploration of PriSM, formed by hydrophobic peptides, as a new paradigm of polypharmacological agents.

Enzyme‐Instructed Intracellular Molecular Self‐Assembly to Boost Activity of Cisplatin against Drug‐Resistant Ovarian Cancer Cells

“…We have been exploring enzyme-instructed molecular self-assembly [5] inside cells, [6] and our recent study shows that intracellular molecular nanofibers promiscuously interact with cytoskeleton proteins [7] yet selectively inhibit cancer cells. [8] Recently, Maruyama et al, [9] Pires and Ulijn, [10] Yang et al, [11] and Wells [12] also reported inhibition of cancer cells by nanofibers formed by the self-assembly of small molecules.…”

“…The genome analysis according to The Cancer Genome Atlas (TCGA) indicates the amplification of CES in certain tumors (e.g., breast and ovarian cancer) ( Figure S23), which not only supports the observation in this work, but also provides useful guidance for treating other cancers based on this approach. This work, together with other emerging evidence, [6][7][8][9][10]12] indicates that enzyme-instructed self-assembly promises a new way for developing combination therapy for cancer treatment. Other than cisplatin, carboplatin has been used as the preferred platinum-based drug [20] and we will use carboplatin for our future work.…”

“…[8] Recently, Maruyama et al, [9] Pires and Ulijn, [10] Yang et al, [11] and Wells [12] also reported inhibition of cancer cells by nanofibers formed by the self-assembly of small molecules. The exceptional selectivity [8] and fundamentally new mechanisms [7,13] of the molecular nanofibers against cancer cells encouraged us to explore the utilization of enzyme-instructed intracellular molecular self- …”

“…This observation agrees with that the intracellular nanofibers of small peptides can interact with actins. [7] To verify the reversibility of the assembly of D-2 inside cells, we treat the SKOV3 cells with D-1 at the concentrations of 20, 50, and 100 μM respectively for 20 h and then we replace the medium containing D-1 with fresh medium for the treatment of an additional 20 hrs. As shown in Figure S12, actin filaments recover after being treated with fresh medium for 20 h when the concentrations of D-1 are 20 and 50 μM.…”

“…Despite the remarkable clinical success of combination therapy (e.g., the combination of cisplatin and paclitaxel), [3] the 5-year relative survival rate of ovarian cancer hardly improved (45% (2004-2010) vs. 45% (1996-2003)) over the past decade. [4e] Thus, there is an urgent need of innovative approach for cisplatin-based combination therapy.We have been exploring enzyme-instructed molecular self-assembly [5] inside cells, [6] and our recent study shows that intracellular molecular nanofibers promiscuously interact with cytoskeleton proteins [7] yet selectively inhibit cancer cells. [8] Recently, Maruyama et al, [9] Pires and Ulijn, [10] Yang et al, [11] and Wells [12] also reported inhibition of cancer cells by nanofibers formed by the self-assembly of small molecules.…”