Co-Treatment of Caco-2 Cells with Doxorubicin and Gold Nanoparticles Produced from Cyclopia intermedia Extracts or Mangiferin Enhances Drug Effects

Abstract

Mangiferin (MGF) is a natural and valuable polyphenol found in significant levels in many plant species, including Cyclopia intermedia (C. intermedia). In a previous study, we synthesized gold nanoparticles (AuNPs) using MGF and a water extract of C. intermedia and reported that these AuNPs have very low cytotoxicity toward a human colon cancer (Caco-2) cell line. Although the study also showed that these biogenic AuNPs in combination with doxorubic (DOX) significantly augmented the cytotoxic effects of DOX in Caco-2 cells, the mechanism of the enhanced effect was not fully understood, and it was also not known if other cell lines would be sensitive to this co-treatment. In the present study, we examined the cytotoxicity of the co-treatment in Caski, HeLa, HT-29, KMST-6 and MDA-321 cell lines. Additionally, we investigated the mechanistic effects of this co-treatment in Caco-2 cells using several assays, including the adenosine triphosphate (ATP), the oxidative stress, the mitochondrial depolarization, the colony formation, the APOPercentage and the DNA fragmentation assays. We also assessed the intracellular uptake of the biogenic AuNPs. The study showed that the biogenic AuNPs were effectively taken up by the cancer cells, which, in turn, may have enhanced the sensitivity of Caco-2 cells to DOX. Moreover, the combination of the biogenic AuNPs and DOX caused a rapid depletion of ATP levels, increased mitochondrial depolarization, induced apoptosis, reduced the production of reactive oxygen species (ROS) and inhibited the long-term survival of Caco-2 cells. Although the study provided some insight into the mechanism of cytotoxicity induced by the co-treatment, further mechanistic and molecular studies are required to fully elucidate the enhanced anticancer effect of the co-treatment.

Anticancer and Drug-Sensitizing Activities of Gold Nanoparticles Synthesized from Cyclopia genistoides (Honeybush) Extracts

“…The drug-sensitizing effects of AuNPs are currently being explored in the fight against cancer to enhance chemotherapeutic drug efficacy while reducing their side effects. Previous studies have demonstrated that co-administration of plant-mediated AuNPs and Dox has the potential to enhance the anti-cancer effects of Dox [6,53]. Of interest, unlike other studies, HB-AuNPs_ci were able to augment the cytotoxicity of Dox when used at a very low and non-toxic dose [4].…”

“…The number of studies describing the use of plant-mediated NPs has increased significantly in the past decade, as well as research describing the possible health benefits of these biogenic NPs in pre-clinical [4,31,35] and clinical studies [28]. As a follow-up to our previous studies [4,6], in the current study we investigated the effect of HB-AuNPs synthesized from C. genistoides on cancer cells either alone or in combination with Dox. Phytochemicals in the HBE served as reducing and capping agents in the synthesis of stable and bioactive HB-AuNPs following optimization of temperature, HBE concentration, and time of synthesis.…”

“…In addition to the selective anticancer activity of the HB-AuNPs synthesized from C. intermedia (HB-AuNPs_ci), the AuNPs demonstrated a unique property of drug sensitization. When co-administered with a chemotherapeutic drug (Dox), HB-AuNPs_ci were reported to increase the biocompatibility of Dox by sensitizing its therapeutic activity at a non-active dose, which might help reduce the drug's bystander effects [4,6]. In the current study, another HB species (C. genistoides) was investigated to determine if species under the same genus will behave in a similar manner; either in AuNPs synthesis or their bioactivity.…”

“…Motivated by the sparsely explored medicinal properties of indigenous South African plants, honeybush (HB), of the genus Cyclopia, became a medicinal plant of interest as a mangiferin (MGF)-rich plant [4]. MGF has many health benefits [5] and is believed to be among the phytochemicals that are responsible for HB's bioactivity [4,6]. Cyclopia are classified into 20 species of flowering plants, examples include C. intermedia, C. genistoides, C. maculata, C. sessiliflora, and C. longifolia that are endemic to the Cape Floristic Region of South Africa.…”

“…Salvia africana-lutea and Sutherlandia frutescens were also used to synthesize AuNPs and silver NPs [23]. HB species were also explored in the synthesis of HB-AuNPs using water extracts from C. intermedia [4,6]. These NPs were reported to inhibit microbial (fungi and bacteria) [22][23][24]26] and cancer cell [4,27] growth, alone or in combination with conventional treatments [4,6].…”