Cryptolepine

Cryptolepine is an orally active multi-potent alkaloid with anti-cancer, anti-bacterial, anti-viral, anti-malarial, anti-inflammatory, anti-hyperglycemic, relieve pain and other properties. Cryptolepine acts as an inhibitor of c-Myc, mTOR, NF-κB, HIF-1, MAPK and an activator of AMPKα1/2. It intercalates into DNA, inhibits topoisomerase II (Top II), disrupts mitochondrial dynamics and induces apoptosis. Cryptolepine also exhibits anti-plasmodial and cholinesterase inhibitory activities. Cryptolepine can be used in research related to tumors ( melanoma, hepatocellular carcinoma, mammary adenocarcinoma, etc.), malaria, inflammatory diseases and diabetes, particularly in studies focused on inhibiting tumor growth and anti-plasmodial infection ^{[1] [2] [3] [4] [6] [7] [8] [9] [10] [11] [12] [13] [14]}.

In Vivo, Cryptolepine (10 mg/kg; i.p.; three times per week; for 24 consecutive days) inhibits melanoma tumor growth in athymic nude mice by disrupting mitochondrial dynamics and biogenesis, resulting in a 68% reduction in tumor volume and a 61% reduction in tumor weight^[1]. Cryptolepine (7.0-112.6 mg/kg/d; s.c.; daily, for 4 days) does not significantly reduce the parasitemia level of P. berghei in mice^[3]. Cryptolepine (10-40 mg/kg; i.p. or p.o.; daily; 4 days) exhibits dose-dependent anti-inflammatory activity in a rat model of acute inflammation without inducing gastric injury^[4]. Cryptolepine (10-40 mg/kg; i.p.) exhibits dose-dependent anti-inflammatory activity in carrageenan-induced rat paw edema models, such as inhibiting LPS-induced microvascular permeability; Cryptolepine (10-40 mg/kg; i.p.) also shows dose-dependent analgesic activity in acetic acid-induced mouse writhing models^[7]. Cryptolepine (5-20 mg/kg; i.p.; once every 2 days; total 7 administrations) dose-dependently inhibits the growth of 4T1 tumors in BALB/c mice, with the tumor growth inhibition (TGI) rate reaching 71.5% in the 20 mg/kg dose group. Its mechanism of action involves the inhibition of HIF-1-mediated glycolysis and ATP production^[8].

In Vitro, Cryptolepine (2.5-7.5 μM; 24 h) induces mitochondrial depletion in A375 and Hs294t melanoma cells in a concentration-dependent manner and activates the AMPKα1/2-LKB1 pathway^[1]. Cryptolepine (2.5-10 μM) inhibits nitric oxide production in LPS-induced RAW 264.7 cells and exerts anti-inflammatory effects by suppressing the DNA-binding activity during NF-κB activation^[4]. Cryptolepine (0.5-2 μM; 24 h) dose-dependently inhibits the levels of p-STAT3 and IL-23 in human hepatocellular carcinoma HepG2 cells treated with 200 ng/mL IL-6 for 24 h^[6]. Cryptolepine (1-20 μM; hypoxic conditions; 24 h) reduces hypoxia-induced HIF-1α protein levels in T47D, 4T1, MCF-7 and MDA-MB-231 breast cancer cells in a time- and dose-dependent manner^[8]. Cryptolepine (0-100 μg/mL; 72 h), extracted from Cryptolepis sanguinolenta, exhibits cytotoxicity against the Jurkat leukemia cell line, with a CC50 value of <62.56 μg/mL^[9]. Cryptolepine (10 μM-1.69×10-4 μM; 48 h) inhibits the viability of late stage IV/V gametocytes of Plasmodium falciparum (NF54), with an IC₅₀ of 1965 nM^[12]. Cryptolepine (0.5-1.2 μM; 48 h) potently inhibits the migration of unstimulated and WNT3a-stimulated DLD1 colorectal cancer cells at IC30(0.5 μM) and IC₅₀ concentrations^[14].

References:
[1]. Pal HC, et al. Cryptolepine inhibits melanoma cell growth through coordinated changes in mitochondrial biogenesis, dynamics and metabolic tumor suppressor AMPKα1/2-LKB1. Sci Rep. 2017;7(1):1498. Published 2017 May 4.
[2]. Ferguson G, et al. Computational Insight into the Intercalating Properties of Cryptolepine. ACS Omega. 2025;10(18):18283-18290. Published 2025 Apr 28.
[3]. Kirby G C, et al. In vitro and in vivo antimalarial activity of cryptolepine, a plant‐derived indoloquinoline[J]. Phytotherapy research, 1995, 9(5): 359-363.
[4]. Tudu CK, et al. Unravelling the pharmacological properties of cryptolepine and its derivatives: a mini-review insight. Naunyn Schmiedebergs Arch Pharmacol. 2023;396(2):229-238.
[5]. Mensah KB, et al. Cryptolepine, the Main Alkaloid of the Antimalarial Cryptolepis sanguinolenta (Lindl.) Schlechter, Induces Malformations in Zebrafish Embryos. Biochem Res Int. 2019;2019:7076986. Published 2019 Jul 8.
[6]. Domfeh SA, et al. Cryptolepine inhibits hepatocellular carcinoma growth through inhibiting interleukin-6/STAT3 signalling. BMC Complement Med Ther. 2021;21(1):161. Published 2021 Jun 2.
[7]. Olajide OA, et al. Anti-inflammatory properties of cryptolepine. Phytother Res. 2009;23(10):1421-1425.
[8]. Zheng Z, et al. Cryptolepine suppresses breast adenocarcinoma via inhibition of HIF-1 mediated glycolysis. Biomed Pharmacother. 2022;153:113319.
[9]. Amissah JN, et al. Mineral Fertilization Influences the Growth, Cryptolepine Yield, and Bioefficacy of Cryptolepis sanguinolenta (Lindl.) Schlt. Plants (Basel). 2022;11(1):122. Published 2022 Jan 1.
[10]. Domfeh SA, et al. The Pharmacologically Active Alkaloid Cryptolepine Activates a Type 1 Interferon Response That Is Independent of MAVS and STING Pathways. J Immunol Res. 2022;2022:8873536. Published 2022 Jul 26.
[11]. Amissah JN, et al. Increasing the planting density of Cryptolepis sanguinolenta (Lindl.) Schlt increased root biomass and cryptolepine yield. Heliyon. 2024;10(10):e30932. Published 2024 May 9.
[12]. Forkuo AD, et al. In vitro anti-malarial interaction and gametocytocidal activity of cryptolepine. Malar J. 2017;16(1):496. Published 2017 Dec 28.
[13]. Quarshie JT, et al. Cryptolepine Suppresses Colorectal Cancer Cell Proliferation, Stemness, and Metastatic Processes by Inhibiting WNT/β-Catenin Signaling. Pharmaceuticals (Basel). 2023;16(7):1026. Published 2023 Jul 19.