Table 3. Anti-cancer Effect of Acriflavine on Selected Tumorsa.
| tumor | cell lines/mice | material/dose | results | ref |
|---|---|---|---|---|
| Brain Cancer | in vitro: 9L, GL261, U87, F98, BTSC | 10%, 25%, and 50% ACF in ACF:CPP:SA | • local ACF therapy: CPP:SA improves survival | (39) |
| in vivo: rats with gliosarcoma 9L | in vivo: local injections of 5 mg/kg/day | • the optimal dose of ACF is 25% in combination with the polymer CPP:SA | ||
| • greater efficiency of local ACF delivery compared to systemic administration | ||||
| Pancreatic Cancer (PDAC) | in vitro: Panc-1, THP-1 | 2.5 μM | • in vitro, ACF reduces EMT | (7) |
| in vivo: mice with PDAC | • in vitro, blocks the activity of TGF-β1 associated with the induction of EMT | |||
| • in vivo: ACF did not affect tumor growth in the fast-growing PDTX model (PAC010), but in a relatively slow-growing model (PAC006), ACF showed significant tumor growth reduction and size stabilization | ||||
| Chronic Myeloid Leukemia (CML) | in vitro: K562, KCL22, LAMA-84, HEK293T, and NIH/3T3 | in vivo: i.p. injections (8 mg ACF/kg/day) for 10 days | • ACF inhibits CML stem cells that are not susceptible to traditional treatment with tyrosine kinase inhibitors | (105) |
| in vivo: mice C57BL/6J-CD45.1 with CML | • ACF may prevent CML recurrences | |||
| primary cells of a CML patient | ||||
| Lung Cancer | in vitro: A549 | ACF-SLN (ACF DL = 31.25 ± 4.21 mg/mL), 0–14 μM | • ACF-SLN showed a stable cytotoxic effect after 48 h, inducing greater apoptosis compared to the free drug | (85) |
| Lung Cancer A549 | in vitro: A549 | in vitro: 0, 1 and 2 μM ACF/48 h | • ACF acts through the caspase-3 activation pathway | (75) |
| in vivo: nude mice with A549 tumor xenograft (BALB / cAnN.Cg-Foxnl nu/CrlNarl) | in vivo: i.p. injection for 6 weeks, 2 mg/kg ACF (60 μL of ACF) | • ACF reduces tumor size in vivo | ||
| Lung Cancer | in vitro: A549 | PMONA NPs (microporous silica with cisplatin and ACF) | • ACF increases the anti-tumor efficacy of cisplatin in vitro | (96) |
| in vivo: A549 xenograft mice | in vitro: 1-20 μM cisplatin | • PMONA loaded with two drugs had a stronger anti-cancer effect than nanoparticles loaded with one drug | ||
| PMONA (2 mg cisplatin/kg) DL (% ACF) = 3.2 ± 1.2 | ||||
| Hepatocellular Carcinoma (HCC) | in vitro: human HCC cells: Mahlavu, SK-Hep1, Hep3B, Huh-7, and PLC/PRF/5 | in vitro: 1, 2, 5, and 10 μM | • ACF acts through the caspase-3 activation pathway | (8) |
| in vivo: Mahlavu cell xenograft mice | in vivo: injection of 2 mg/kg daily for 5 weeks | • inhibits the viability of HCC cell lines in a dose-dependent manner | ||
| • inhibits the growth of neoplastic cells in vivo | ||||
| Cervical Cancer | in vitro: HeLa | Nonoplatforma: ACF@PCN-222@MnO2-PEG | • enhancement of PDT | (76) |
| in vivo: female Kunming mouse model with U14 cells | ||||
| Colorectal Cancer (CRC) | primary tumor cell cultures from patients | in vitro | • ACF is more active against CRC (IC50 = 1.38 μM) than against OC (IC50 = 4.23 μM) and CLL (IC50 = 2.58 μM) | (72) |
| • ACF is an inhibitor of topoisomerases I and II | ||||
| Colitis-Associated Colon Cancer (CAC) | mice Balb/C | in vivo: injections 2 mg/kg/day | • ACF reduces vascularity growth and tumor progression | (38) |
| • ACF acts on HIF-1 | ||||
| Colorectal Cancer (CRC) | SW480, HCT116, LS174T | in vitro: 0.07, 0.15, 0.31, 0.62, 1.25, 2.5, and 5 μM/72 h | • ACF enhances the effect of 5-fluorouracil better than irinotecan | (79) |
| • it exhibits a different mechanism than the suppression of HIF-1α and topoisomerase II expression (their levels were unchanged) | ||||
| Colorectal Cancer | in vitro: CT26 | DOX-ACF@Lipo (encapsulated DOX and ACF in liposomes) | • DOX-ACF@Lipo cellular uptake is dependent | (8) |
| in vivo: Balb/c mice with the CT26 tumor | in vitro: DOX-ACF@Lipo and DOX@Lipo ([DOX] = 0.047, 0.236, 0.47, 0.94, 2.36, and 4.7 μg/mL, [ACF] = 0.1, 0.5, 1, 2, 5, and 10 μg/mL)/24 h | • a better therapeutic effect was achieved by DOX-ACF@Lipo at different concentrations compared to DOX@Lipo | ||
| in vivo: i.v. injections of 5 mg/kg | • in vivo: DOX-ACF@Lipo, tumor volume was 28.9%; DOX@Lipo, tumor volume was 32.6% | |||
| Colorectal Cancer | in vitro: CT26 | ACF@MnO2 | • ACF@MnO2 can reduce cell viability more effectively than free acriflavin or free MnO2 in the presence of X-rays, significantly less metastasis in the liver was observed | (92) |
| Breast Cancer | in vivo: mice with 4T1 | i.v. injection, 3 mg/kg/14 days | • ACF@MnO2 can effectively suppress the expression of metastatic proteins (VEGF and MMP-9) | |
| Breast Cancer | MDA-MB-231, MDA-MB-435 | in vivo: 4 mg/kg/day i.p. | • ACF acts on HIF-1 by reducing the expression of LOX and LOXL proteins (responsible for metastasis), destroying metastatic niches of breast cancer | (80) |
| mice with MDA-435 | ||||
| Breast Cancer | mouse breast cancer cells (4T1 cells) | CSP-ACF nanoparticles | • very low drug concentration (5 μg /mL) in the form of CSP nanoparticles can lead to apoprosis of more than 60% of cancer cells | (74) |
| in vitro: 0–5 μg/mL | • ACF alleviates hypoxia and makes a patient more sensitive to radiotherapy | |||
| • CSP-ACF nanoparticles lead to a decrease in VEGF, fewer tumor microvessels and more cell apoptosis | ||||
| Breast Cancer | in vitro: 4T1 | ACF-LNC | • higher efficiency of ACF-LNC compared to free ACF | (83) |
| in vivo: mice with 4T1 | in vivo: 5 mg/kg | • the use of ACF-LNC allowed reduction of the number of administrations compared to free ACF (from 12 to 2 injections) in vivo | ||
| Breast Cancer | mice BALB/c with 4T1 | in vivo: ACF 2 mg/kg i.p. | • ACF increases the antitumor activity of sunitinib, lowers the expression of VEGF and TGF-β, and reduces tumor vascularization, leading to its apoptosis | (78) |
| Melanoma | B16-F10 and 4T1 | 5, 10, 20, and 30 μM | • ACF improved the effectiveness of cancer immunotherapy in combination therapy with TRP-2 and anti-PD-1 antibody | (111) |
| Melanoma | SK-MEL-28, IGR37, and B16/F10 murine melanoma cells | in vitro: 0, 2.5, and 5 μM | • ACF induces melanoma cell death under conditions of normoxia | (10) |
| • ACF disrupts glucose metabolism by down-regulating PDK1 | ||||
| • inhibits the phosphorylation of AKT and RSK2 | ||||
| • targets the activation of transcription factor 4 (ATF4) | ||||
| • inhibits the expression of the transcription factor MITF (the factor responsible for the acts of induction of HIF-1 transcription) | ||||
| Perihilar Cholangiocarcinoma | SK-ChA-1 | • liposomal ACF sensitizes tumor cells to PDT | (73) | |
| • ACF inhibits HIF-1 and topoisomerases I and II | ||||
| Epidermal Cancer | A431 | in vitro: ACF encapsulated in the aqueous core of the liposomes containing the ZnPC photosensitizer | • action of free or liposomal ACF improves the efficacy of PDT | (86) |
| Osteosarcoma | MG63 | in vitro: 0, 0.1, 1, 5, and 10 μM | • ACF (0–10 μM) inhibits the growth of osteosarcoma cells in a dose-dependent manner | (100) |
| • ACF induces tumor apoptosis via both HIF-1α-dependent and HIF-1α-independent pathways | ||||
Abbreviations used: F98, 9L, GL261, and U87, human glioma cell lines; BTSCs, human primary brain tumor stem cells; CPP:SA, biodegradable polyanhydride poly(1,3-bis[p-carboxyphenoxy]propane-co-sebacic acid); Panc-1, human pancreatic cancer cells; THP-1, human monocytic cell line; EMT, epithelial-to-mesenchymal transition; PDTX, human PDAC xenografts: PAC006 (classical type, moderately differentiated and slow progression) and PAC010 (quasi-mesenchymal type, poorly differentiated and faster growth); K562, human erythroleukemic cell line; KCL22, human myeloid leukemia cell line; LAMA-84, human chronic myeloid leukemia cell line; HEK293T, human embryonic kidney 293 cells; NIH/3T3, cell lines of mouse embryonic fibroblasts; CML, myeloid leukemia; A549, adenocarcinomic human alveolar basal epithelial cells; ACF-SLN, solid lipid nanoparticles containing ACF; PMONA, cisplatin microporous organosilica nanoparticles with ACF; Mahlavu, SK-Hep1, Hep3B, Huh-7, and PLC/PRF/5, human hepatocellular carcinoma cells; HeLa, epitheloid cervical carcinoma; SW480, human colon adenocarcinoma; HCT116, human colon cancer cell line; LS174T, human intestinal cell line; DOX, doxorubicin; CT26, murine colorectal carcinoma cell line; 4T1, breast cancer cell line; VEGF, vascular endotherial growth factor; MMP-9, matrix metalloproteinase 9; MDA-MB-231 and MDA-MB-435-human breast adenocarcinoma; LOX, lysyl oxidase proteins; LOXL, lysyl oxidase-like proteins; CSP, Cu2-xSe@PtSe, type of yolk–shell nanosensitizer; ACF-LNC, lipid nanocapsules containing acriflavine; TGF-β, transforming growth factor beta; B16-F10, mouse melanoma cells; TRP-2, tyrosinase-related protein-2; PD-1, programmed death receptor 1; SK-MEL-28 and IGR37, human melanoma cells; PDK1, pyruvate dehydrogenase kinase 1; AKT, protein kinase; RSK2, serine/threonine kinase ribosomal S6 kinase 2; ATF4, activating transcription factor 4; MITF, microphthalmia-associated transcription factor; SK-ChA-1, human cholangiocarcinoma cells; A431, squamous carcinom cell line; MG63, human osteosarcoma cell line; i.p., intraperitoneal; i.v., intravenous.