Table 1.

Phenothiazines effecting cell membrane integrity and their respective anti-tumor activities.

Phenothiazines	Anti- tumor activity	Cancer Types	Effects on Membrane Integrity	In Vivo/Vitro Efficacy
Chlorpromazine	Induces cytotoxic autophagy in glioblastoma cells via ER stress and the unfolded protein response, causes mitotic arrest through KSP/Eg5 inhibition (50), affects CcO, complex IV in chemo resistant cells in GBM (51).	Leukemia (52), GBM (51), EC (53)	Reduces the association of K-Ras with the plasma membrane and increases its exchange between membrane and cytoplasmic pools leading to apoptosis (54).	In vitro: CPZ suppresses in vitro wound healing of PANC-1 GFP-K-Ras (G12V) cells and inhibits colony formation in soft agar (54). In vivo: cell-cycle arrest at the G2/M phase in rat C6 glioma cells, selectively inhibits growth and proliferation of chemo resistant glioma cells expressing COX4-1 (51).
Fluphenazine	Inhibits sphingomyelinase and causes cellular sphingomyelin accumulation (55), targets the Akt and Wnt signaling, induces DNA alterations and affects migration (8, 36, 56).	liver (36), oral and ovarian cancer (36), LC (8, 56), TNBC (56).	Alters membrane integrity by perturbing lipid bilayer structure and affecting membrane dynamics (23). Potentially, affects membrane repair processes (36).	In vitro: Induced G0/G1 cell cycle arrest and mitochondria mediated intrinsic apoptosis (8). In vivo: induced cancer cell apoptosis in a TNBC subcutaneous xenograft mouse model (56).
Prochlorperazine	Inhibits the P2X7 receptor on plasma membrane (57), enhance the efficacy of anti-tumor mAbs (58), Blocks D2 dopamine receptors (57).	TNBC (58), LC (59) GBM (57).	Calcium channel blockade (57), disrupts the structural organization between lipids and proteins in microsomal membranes (59).	In vitro: PCZ exhibits a synergistic effect on cancer cell death, both in vitro and in xenograft models, and improves the overall survival of mice (59). In vivo: alters EGFR distribution, reversibly inhibit the endocytosis of membrane proteins targeted by therapeutic monoclonal antibodies (58).
Promethazine	Initiating of autophagy-associated apoptosis through AMPK activation and PI3K/AKT/mTOR inhibition (60), promotes apoptosis by suppressing the PI3K/AKT signaling pathway (61), hinders proliferation and induces autophagy by increasing LC3II and p62 levels in cancer cell lines (62).	CML (60), CRC (61), SCLC (63), PDAC (62).	Indicates an early phosphatidylserine externalization followed by later plasma membrane permeabilization (60).	In vitro: Exhibits potent and specific cytotoxicity against various leukemia cell types through the activation of AMPK and the inhibition of the PI3K/AKT/mTOR pathway (60), impedes cell proliferation and triggers autophagy by elevating the levels of LC3II and p62 in human pancreatic ductal adenocarcinoma (PDAC) cell lines (62). In vivo: Reduces the growth of both mouse and human SCLC by inducing cell death (63).
Thioridazine	Induces eryptosis (64), targeting and inhibiting the PI3K/Akt/mTOR/p70S6K signaling pathway, leading to cell cycle arrest, apoptosis, and cytotoxic effects (65, 66), modulates endothelial cells and impedes angiogenesis via the VEGFR-2/PI3K/mTOR pathway, triggers autophagy by upregulating AMPK activity (67).	TNBC (65), cervical and endometrial cancer (34), OC (35), GBM (67)	Membrane permeabilization (66); triggering of cell membrane scrambling with increase of phosphatidylserine abundance at the cell surface, Thioridazine is partially effective by activation of p38 kinase and by increase of cytosolic Ca2+ concentration (64).	In vitro: induces autophagy in glioblastoma multiforme (GBM) cell lines and upregulates AMPK activity (67), inhibited the viability and migration of TNBC cells (65). In vivo: Strong antiproliferative effects on B16 melanoma cells, inducing DNA fragmentation and increasing the expression of Caspase-3, a key mediator of apoptosis (68), TZ reduces growth and angiogenesis in ovarian cancer by reducing the phosphorylation of VEGFR-2 and inhibiting PI3K/mTOR signaling in xenografts (35).
Trifluoperazine	Disrupts ANXA-mediated plasma membrane repair (23), induces G0/G1 cell cycle arrest and inhibit proliferation and apoptosis of tumor cells (69), suppress tumor cell growth (70, 71).	Metastatic melanoma (69), TNBC (70), GBM (71)	disrupts ANXA-mediated plasma membrane repair (23), reduces plasma membrane fluidity by intercalating into the lipid bilayer, thins the membrane bilayer and making it more fragile (23, 69).	In vitro: Induced G0/G1 cell cycle arrest via decreasing the expression of both cyclinD1/CDK4 and cyclin E/CDK2 in TNBC (70), decreased cell viability and proliferation, colony formation and spheroid growth on metastatic melanoma (69). In vivo: Increased the radiosensitivity of GBM, resulting in increased tumor cell death and prolonged animal survival (71), cytotoxic effects on melanoma brain metastases (69)