Paraptosis‐Inducing Nanomedicine Overcomes Cancer Drug Resistance for a Potent Cancer Therapy

Abstract

Most chemotherapeutic drugs and their nanomedicine formulations exert anticancer activity by inducing cancer cell apoptosis. However, cancer cells inherently have and acquire many antiapoptosis mechanisms, causing cancer drug resistance and poor prognoses in patients. Herein, a potent paraptosis‐inducing nanomedicine is reported that causes quick nonapoptotic death of cancer cells, overcoming apoptosis‐based resistance and effectively inhibiting drug‐resistant tumor growth. The nanomedicine is composed of micelles made from an amphiphilic 8‐hydroxyquinoline (HQ)‐conjugate block copolymer with polyethylene glycol. Cu2+ can catalyze the hydrolysis of the HQ conjugation linker and liberate HQ, and these molecules can form the complex Cu(HQ)2, a strong proteasome inhibitor effective at inducing cell paraptosis. In vivo, the Cu2+‐responsive HQ‐releasing micelles respond to elevated tumor Cu2+ levels or externally administered Cu2+ and effectively inhibit the growth of human breast adenocarcinoma doxorubicin‐resistant (MCF‐7/ADR) tumors. Compared with other nanomedicines that overcome drug resistance via delivering several agents or even siRNA, this paraptosis‐inducing nanomedicine provides a simple but potent approach to overcoming cancer drug resistance.

Pathways to Paraptosis After ER Photodamage in OVCAR‐5 Cells

“…Mitogen‐activated protein kinases (MAPKs), including c‐Jun N‐terminal kinases (JNKs) have been implicated . The initiation of paraptosis by many drugs is associated with a misfolded protein response involving the ER . It appears that paraptosis can be a pathway to eradication of cells with an impaired apoptotic program .…”

“…The initiation of paraptosis by many drugs is associated with a misfolded protein response involving the ER . It appears that paraptosis can be a pathway to eradication of cells with an impaired apoptotic program . Studies reported here were designed to further characterize the elements of paraptosis in OVCAR‐5 cells.…”

Copper as the Target for Anticancer Nanomedicine

“…[94,141] However, clinical use of copper-based cytotoxins is still limited due to their very low water-solubility and instability in in vivo transportation. An important character of some copper-based cytotoxins, e.g.…”

“…[135] Adv. [141] Most chemotherapeutics and their nanoformulations kill cancer cells by inducing caspase-dependent apoptosis. 2019, 2 In addition, Greish et al reported that curcumin-copper complex encapsulated in poly(styrene-co-maleic acid) micelles could abolish the growth of triple-negative breast cancer in vivo without overt side effects.…”

“…[141] Most chemotherapeutics and their nanoformulations kill cancer cells by inducing caspase-dependent apoptosis. [141] [142] As another kind of programmed cell death, paraptosis bypasses caspase pathways and is immune to the anti-apoptosis mechanisms.…”