The natural compound oblongifolin C inhibits autophagic flux and enhances antitumor efficacy of nutrient deprivation

Abstract

Metabolic stress induces autophagy as an alternative source of energy and metabolites. Insufficient autophagy in nutrient-deprived cancer cells would be beneficial for cancer therapy. Here, we performed a functional screen in search of novel autophagy regulators from natural products. We showed that oblongifolin C (OC), a natural small molecule compound extracted from Garcinia yunnanensis Hu, is a potent autophagic flux inhibitor. Exposure to OC results in an increased number of autophagosomes and impaired degradation of SQSTM1/p62. Costaining of GFP-LC3B with LysoTracker Red or LAMP1 antibody demonstrates that autophagosome-lysosome fusion is blocked by OC treatment. Furthermore, OC inhibits lysosomal proteolytic activity by altering lysosomal acidification and downregulating the expression of lysosomal cathepsins. Importantly, OC can eliminate the tolerance of cancer cells to nutrient starvation. Starvation dramatically increases the susceptibility of cancer cells to OC-induced CASP3-dependent apoptosis in vitro. Subsequent studies in xenograft mouse model showed that OC has anticancer potency as revealed by increased staining of cleaved CASP3, LC3 puncta, and SQSTM1, as well as reduced expression of lysosomal cathepsins. Combined treatment with OC and caloric restriction potentiates anticancer efficacy of OC in vivo. Collectively, these data demonstrated that OC is a novel autophagic flux inhibitor and might be useful in anticancer therapy.

Molecularly Imprinted Polymers for Selective Extraction of Oblongifolin C from <em>Garcinia yunnanensis</em> Hu

“…Previous phytochemical investigations in our group showed that oblongifolin C (OC) and guttiferone K (GK) are two mainly polyisoprenylated benzophenone derivatives (PPAPs) from G. yunnanensis Hu [1]. The results of our studies revealed further that OC and GK are multi-therapeutic agents with anti-inflammatory and anti-cancer properties [1,[3][4][5][6][7]. Emerging evidence clearly indicated that OC and GK are promising candidates for developing novel treatments for infection or cancer and large amounts of these compounds are needed for further investigations, especially for animal studies [5].…”

“…The results of our studies revealed further that OC and GK are multi-therapeutic agents with anti-inflammatory and anti-cancer properties [1,[3][4][5][6][7]. Emerging evidence clearly indicated that OC and GK are promising candidates for developing novel treatments for infection or cancer and large amounts of these compounds are needed for further investigations, especially for animal studies [5]. Without published synthetic route, OC or GK was usually isolated from plants using conventional techniques [1,8] such as repeated silica gel column chromatography, MCI column chromatography, medium-pressure preparative liquid chromatography (MPLC), and preparative HPLC, all of which included complicated, inefficient, and time-consuming operations.…”

Honokiol exhibits enhanced antitumor effects with chloroquine by inducing cell death and inhibiting autophagy in human non-small cell lung cancer cells

“…During this process, autophagosomes engulf damaged proteins and defective organelles and then fuse with lysosomes for degradation (9). Finally, the unnecessary proteins are removed, the flawed organelles are eliminated and the cell growth is sustained during conditions of stress through autophagy.…”

Autophagy-associated Targeting Pathways of Natural Products during Cancer Treatment

“…Up till now, many natural products have been reported to able to cause cancer cell death by regulating the functional status or signal pathways of autophagy (Ajabnoor et al, 2012;Lao et al, 2014;Larocque et al, 2014). In this article, the application of representative natural products in cancer treatments and their action modes associated with autophagy signal pathway have been reviewed and discussed in an attempt to inspire the promising treatment strategies for cancers in the future.…”

“…Thereby, natural compounds are expected to become potential effective drugs for the prevention and treatment of cancers in the future. In vitro and in vivo studies have shown that many dietary agents from fruits, tea and some herbs with both medicinal and food functions are able to fight against and prevent cancers via regulating cellular fate through apoptosis and autophagy (Kallifatidis et al, 2013;Kma, 2013;Lachumy et al, 2013;Zhong et al, 2013;Lao et al, 2014;Larocque et al, 2014).…”