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BACKGROUND One of the apoptotic resistance mechanisms in breast cancer stem cells (CSCs) is designed by the existence of tumor-associated macrophages (TAMs), type 2 macrophages. TAMs enhance the apoptotic resistance of CSCs by extremely decreasing low levels of inducible nitric oxide (iNO) and a reactive oxygen intermediate (ROI). On the other hand, heat shock protein-70 (Hsp-70) expression may modulate TAMs to upregulate those molecules. Typhonium flagelliforme (TF) tuber extract has an apoptotic activity through increasing iNO and ROI levels of cancer cells. However, the role of TF in increasing the Hsp-70 expression of TAMs leading to apoptosis improvement remains unclear. TAMs were produced by coculturing the human breast cancer-derived peripheral blood mononuclear cells with the CSCs. TAMs were assigned into two treatment groups consisting of one treatment group (treated by TF at 50.89 μg/ml) and the control group (medium administration only). The expression of Hsp-70 was analyzed by immunocytochemistry. This study found that Hsp-70 expression was shown to be significantly increased in TAMs. In conclusion, TF may promote the increase of Hsp-70 expression in TAMs. Hsp-70 as a promising drug target in cancer therapy for reducing resistance to cancer therapy has the potential to be developed and investigated further.
Extraction of TF
TF (Araceae) herbs were collected from Semarang, Central Java, Indonesia (latitude 7.0051°S and longitude 110.4381°E). Authentication was conducted at the Plant Systematic Laboratory, Faculty of Biology, Universitas Gadjah Mada. 360.4g of the fresh plant was harvested and washed thoroughly with
circulating distilled water, followed by tubers being chopped into small pieces and dried (Memmert, Models 100–800, Schwabach, Germany). The dried tubers were powdered and macerated with hexane for 3 days to remove the nonpolar fractions before being treated with dichloromethanes for 7 days with intermittent shaking (Edmund Buchler Shaker, Model KS-15, Hechingen, Germany) and then filtered and vacuum-evaporated using a rotary evaporator (Buchi, R-210, Postfach, Switzerland) (Suzery et al., 2020).
RESULTS Cancer cells have high expression of chaperones, particularly Hsp-70, which promote proliferation and escape from programmed cell death (Albakova et al., 2020; Komarova et al.,
2020). Naturally, Hsp-70 can be released into the extracellular milieu by cancer cells without an additional trigger (Seclì et al., 2021). In addition, the higher level of Hsp-70 in cancer cells is associated
with more chaperone molecules in the microenvironment of CSCs (Kabakov et al., 2020; Vega et al., 2008). Furthermore, TAMs constitute the tumor microenvironment cellular population which strongly influence cancer cell tumorigenicity including promoting cancer progression, development, metastasis, cancer stemness, and escape immune surveillance (Ge et al., 2020).
Keywords: Apoptosis resistance, CSCs, Hsp-70, TAM, Typhonium flagelliforme.