Medicinal plants from the Plectranthus genus are a valuable source of natural products such as diterpenes [1,2]. Mitochondrial dysfunctions (MD) have been associated with several pathologies such as ROS increase and uncontrolled Mycobacterium tuberculosis (Mtb) replication [3,4]. The electrochemical gradient produced by mitochondria generates the mitochondrial membrane potential (MMP), which is a key parameter for evaluating MD [4]. Previous works have reported the cytotoxicity of Plectranthus diterpenoids and pointed their potential against M. smegmatis [2,5].
In this work, diterpenoids from P. ornatus Codd. (previously isolated [1,2]) were evaluated for their cytotoxicity and for the mechanisms of cell death associated with MD in A549 cell line (human lung adenocarcinoma). One halimane HAL: (11R*,13E)-11-acetoxyhalima-5,13-dien-15-oic acid) and two labdane diterpenes PLEC: Plectrornatine C and the MRC: 1,6-di-O-acetylforskolin:1,6-di-O-acetyl-9-deoxyforskolin (1:1). Our pioneer study showed that only HAL and PLEC were cytotoxic (IC50=60 and 8 μg.mL-1, respectively).
Also, the ROS level observed after 1h was significantly higher (p < 0.01) with HAL and this effect was maintained for up to 48h. All compounds were able to decrease mtDNA copy number, but only HAL increased MMP and exhibited DNA damage of 8.78 lesions per 10 kb (ND5 region).
In conclusion, HAL has a cytotoxic effect associated with MD on lung cancer cells, that may be further evaluated on the Mtb replication mechanism. Additional studies are ongoing, aiming to unveil the coexistence of tuberculosis and lung cancer that has remained controversial, since the middle of the 19th century.
[1] Rijo P., et al. Magn Reson Chem MRC. 2005;43(7):595–8.
[2] Rijo P., et al. Biochem Syst Ecol. 2007 Apr;35(4):215–21.
[3] Duan L., et al. J Immunol. 2002;169(9):5181–7.
[4]Sakamuru S., et al. Methods Mol Biol. 2016;1473:17–22.
[5] Burmistrova O., et al. J Nat Prod. 2013;76(8):1413–23.