Capsicodendrin from Cinnamosma fragrans Exhibits Antiproliferative and Cytotoxic Activity in Human Leukemia Cells: Modulation by Glutathione

Abstract

Capsicodendrin (CPCD, 1), an epimeric mixture of a dimeric drimane-type sesquiterpene, is one of the major compounds present in the three endemic species of Madagascan traditional chemopreventive plants: Cinnamosma species ( C. fragrans, C. macrocarpa, and C. madagascariensis). Despite the popular use of Cinnamosma in Madagascan traditional medicine and the reported antiproliferative properties of CPCD, elucidation of its mechanism(s) of action is still to be accomplished. In the present study, CPCD at low micromolar concentrations was cytotoxic and induced apoptosis in human myeloid leukemia cells in a time- and concentration-dependent manner. The activity of CPCD in HL-60 and K562 cells was modulated by glutathione (GSH), since depletion of this intracellular thiol-based antioxidant with buthionine sulfoximine resulted in significantly ( p < 0.05) greater potency in antiproliferation assays. GSH depletion also significantly potentiated the cytotoxic activity in CPCD-treated human HL-60 cells. Single-cell gel electrophoresis (Comet) assays revealed that GSH depletion in HL-60 cells enhanced the formation of DNA strand breaks in the presence of CPCD. Although CPCD does not contain an obvious Michael acceptor in its structure, H NMR analyses indicated that cinnamodial (2), a monomer of CPCD, was formed within a few hours when dissolved in DMSO- d and interacts with GSH to form a covalent bond via Michael addition at the C-7 carbon. Together the results strongly suggest that 2 is responsible for the DNA-damaging, pro-apoptotic, and cytotoxic effects of CPCD and that depletion of GSH enhances overall activity by diminishing covalent interaction between GSH and this 2-alkenal decomposition product of CPCD.

Insecticidal and Antifeedant Activities of Malagasy Medicinal Plant (Cinnamosma sp.) Extracts and Drimane-Type Sesquiterpenes against Aedes aegypti Mosquitoes

“…Previously, we demonstrated that the weakly-bioactive dimer 7 dissociated into highly bioactive monomers of 1, and the presence of DMSO enhanced this dissociation [45]. Consistent with the previous study, we found that 7 was significantly more larvicidal when its stock solution was prepared in DMSO vs. acetone, suggesting 7 is a pro-insecticide that requires dissociation into 1 before becoming toxic.…”

“…In larvae (Figure 3D), at the screening concentration (100 µM), WARB ( 10 ), CDIAL ( 1 ), and CFRAG ( 2 ) were among the most toxic, while POLYG ( 9 ) and CPCD ( 7 ) were moderately efficacious; CML ( 4 ), UGAN ( 5 ), CMOS ( 3 ), DRIM ( 6 ), and CFGL ( 8 ) were among the least toxic. Previously, we found that 7 dissociated into monomers of 1 in DMSO [45]. Thus, in a parallel experiment, we directly compared the larvicidal efficacy of 7 when dissolved as a stock solution in acetone vs. DMSO.…”

Stop the crop: insights into the insecticidal mode of action of cinnamodial against mosquitoes

“…As such, when CPCD was dissolved in DMSO, it displayed similar inhibition as CDIAL. On the other hand, when CPCD was dissolved in acetone, it lacked effects on crop contractions, which confirms our earlier findings that CPCD has limited bioactivity in its dimeric form (Inocente et al, 2019;Karmahapatra et al, 2018). The strong inhibition of crop contractions by the dialdehydes CDIAL, POLYG and WARB, but not lactone derivatives with similar structures (CMOS, CML, and DRIM), indicate that electrophilic aldehydes are important in the bioactivity of drimane sesquiterpenes against mosquito visceral muscle.…”

“…In addition to CDIAL, other natural drimane sesquiterpenes inhibited the spontaneous contractions of the crop, including CPCD, POLYG, and WARB. CPCD is a dimeric form of CDIAL that rapidly converts into CDIAL monomers in the presence of DMSO (Karmahapatra et al, 2018). As such, when CPCD was dissolved in DMSO, it displayed similar inhibition as CDIAL.…”

Total Synthesis of Cinnamodial-Based Dimer (−)-Capsicodendrin

“…In this report, Harinantenaina and Takaoka also revealed that capsicodendrin ( 3 ) is a mixture of C12′-epimers of cinnamodial-based hemiacetal dimer and not a tetramer of cinnamodial ( 1 ), as proposed in its original isolation report . Importantly, biological activity studies of capsicodendrin ( 3 ) revealed that it exhibits antiproliferative and cytotoxic activity in human leukemia cells . Notable angiogenesis inhibition by capsicodendrin ( 3 ) was also reported .…”