Development of apoptosis-inducing polypeptide via simultaneous mitochondrial membrane disruption and Ca2+ delivery

Strategies of Perturbing Ion Homeostasis for Cancer Therapy

“…Chloride influx Mitochondria-dependent apoptosis [40] Potassium Helical polypeptide Potassium efflux ER stress-mediated apoptosis [23] Valinomycin Potassium efflux Restoration of T cell immunity [31] Salinomycin Potassium efflux Suppression of Wnt pathway [6] Gramicidin A Potassium efflux Downregulation of CD47 [49] Calcium Helical polypeptide Calcium overload Mitochondria-dependent apoptosis [24] Calcium NPs Calcium overload Mitochondria-dependent apoptosis [59,[62][63][64] Tumor calcification [59,64] Zinc Clioquinol Zinc overload Inhibiton of NF-𝜅B pathways [ 68,115] Disulfiram Zinc overload Lysosomal disruption [69] Zinaamidole A Zinc overload Non-apoptotic cell death [11] Zinc NPs Zinc overload Oxidative stress-mediated apoptosis [ 71,73,74,77] PAC-1 Zinc depletion Autophagic cell death [ 75,116] Ferroptosis via disruption of iron homeostasis [76] VEGF inhibition [79] Manganese Manganese NPs Manganese overload Chemodynamic activity via Fenton-like reaction [84][85][86][87][88]117] MnO x nanospikes-nanovaccine Manganese overload Ferroptosis via Fenton-like reaction [89,90] Activation of cGAS/STING pathway [91] Ferroptosis-mediated ICD [90] Iron Tannic acid-based NP Iron overload Ferroptosis via Fenton reaction [21] Salinomycin analogue Iron overload Ferroptosis in cancer stem cells [9] Oxidized Starch Iron overload Ferroptosis via Fenton reaction [97] Iron NPs Iron overload Ferroptosis via Fenton reac...…”

“…For example, Ha and coworkers developed a helical polypeptide-based calcium ionophore by tethering the diethylenetriaminepentaacetic acid moiety in order to transport calcium ions (Figure 6a). [24] An ROS-cleavable apoptosis-inducing peptide (RAP) composed of a mitochondria-destabilizing moiety and a calcium-delivering moiety, simultaneously destabilized mitochondrial membranes and elevated the intracellular calcium concentration, thereby synergistically stimulating apoptosis (Figure 6a). [24] Moreover, excessive oxidative stress fostered by RAP downregulated the expression of caveolin-1 and matrix metalloproteinase-2/9, thus suppressing cell migration and invasion.…”

“…[24] An ROS-cleavable apoptosis-inducing peptide (RAP) composed of a mitochondria-destabilizing moiety and a calcium-delivering moiety, simultaneously destabilized mitochondrial membranes and elevated the intracellular calcium concentration, thereby synergistically stimulating apoptosis (Figure 6a). [24] Moreover, excessive oxidative stress fostered by RAP downregulated the expression of caveolin-1 and matrix metalloproteinase-2/9, thus suppressing cell migration and invasion. [24] Calcium signaling plays essential roles in regulating both innate and adaptive immune responses.…”

“…[24] Moreover, excessive oxidative stress fostered by RAP downregulated the expression of caveolin-1 and matrix metalloproteinase-2/9, thus suppressing cell migration and invasion. [24] Calcium signaling plays essential roles in regulating both innate and adaptive immune responses. [57] For calcium signaling in T cells, the elevated intracellular calcium level allows T cells to kill cancer cells in an antigen-specific manner, which is a promising approach to overcome the low potency of cancer immunotherapy.…”

“…[4] Recently, various approaches for perturbing ion homeostasis have been intensively investigated to develop new and effective anticancer DOI: 10.1002/adtp.202100189 agents ranging from prevalent ions to trace metal ions. [4,5] Various ion homeostasisperturbing agents, such as small moleculebased ionophores [6][7][8][9][10][11][12] or chelators, [13][14][15][16] metal ion nanoparticles (NPs), [17][18][19][20][21][22] and peptide-based ionophores, [23,24] can trigger programmed cell death and also boost antitumor immunity by activating or deactivating specific signaling pathways (Figure 1). Prevalent ions such as chloride, calcium, and potassium have been attractive targets to disturb ion homeostasis.…”