Curcumin increases the sensitivity of K562/DOX cells to doxorubicin by targeting S100 calcium‑binding protein A8 and P‑glycoprotein

Abstract

The development of multidrug resistance (MDR) has seriously impeded the efficacy of drug treatment of chronic myeloid leukemia (CML). Recent studies have indicated that S100 calcium-binding protein A8 (S100A8) is associated with the occurrence and development of MDR. Traditional Chinese medicine may provide drugs with the potential to be used as multidrug resistance reversal agents with low toxicity and multi-target characteristics. The present study selected K562/DOX cells, a CML drug-resistant cell line, as a research model, and aimed to examine whether curcumin was able to reverse the resistance to doxorubicin (DOX), and elucidate the underlying molecular mechanisms. An MTT cytotoxicity assay indicated that curcumin at 0.5–2 µM reversed DOX resistance with a reversal index of 1.3–9.3. Western blot analysis revealed that curcumin treatment caused a downregulation of the expression of P-glycoprotein (P-gp) and S100A8 in a dose- and time-dependent manner. To study the internal association between S100A8 and P-gp, and the S100A8 role in drug resistance reversal, an RNA knockdown assay was conducted; however, S100A8 did not regulate the expression of P-gp or vice versa. After inhibiting the expression of S100A8 with specific small interfering RNA (si-S100A8), the sensitivity of K562/DOX cells to DOX was enhanced. In addition, si-S100A8 did not increase the intracellular accumulation of DOX, but increased the intracellular free calcium ion content, and the expression and activity of apoptosis-associated proteins, thereby inducing apoptosis. In conclusion, the present study suggested that inhibition of S100A8 expression increased DOX-induced apoptosis, and curcumin acted independently on S100A8 and P-gp to exert its drug resistance reversal effects

Polychemotherapy with Curcumin and Doxorubicin via Biological Nanoplatforms: Enhancing Antitumor Activity

“…The increased sensitivity of cancer cells to DOX chemotherapy upon S100A8 inhibition is not due to enhanced accumulation of DOX, but also due to enhanced intracellular free calcium ion content and overexpression of proapoptotic proteins. Curcumin (0–32 μM) as a potential antitumor agent, reduces expression of S100A8 and P-gp in a time- and dose-dependent manner to promote DOX accumulation and induce apoptosis in leukemia cells [ 138 ]. These studies demonstrate that drug transporters participate in DOX resistance and they are potential targets of curcumin in providing chemosensitivity.…”

Nrf2 Signaling Pathway in Chemoprotection and Doxorubicin Resistance: Potential Application in Drug Discovery

“…Currently, two major obstacles are considered for cancer chemotherapy with DOX including A) DOX resistance, and B) dose-dependent toxicity [7][8][9]. The toxicity of DOX against normal cells has a negative impact on its efficacy in cancer therapy, since high dose of DOX cannot be administered to cancer patients to overcome resistance.…”

Targeting Drug Chemo-Resistance in Cancer Using Natural Products

“…Moreover, combination of polyphenols such as EGCG, tannic acid, and curcumin exhibited a high synergistic effect with doxorubicin via attenuating the P-gp function in human colon cancer and leukemia cell lines [102]. Moreover, the Western blot analysis shows a reduction in P-gp levels after applying curcumin treatment in K562/DOX cells as well as enhances the sensitivity of the cells to the chemotherapy [113]. Moreover, the expression of P-gp was decreased in A2780/Taxol cells when curcumin and piperine was combined in solid lipid nanoparticle form [114].…”

“…LRP also causes resistance to compounds including alkaloids, anthracyclines, and epipodophyllotoxin. In addition to this, LRP also causes resistance to many drugs, which include doxorubicin (Dox), vincristine, cisplatin, and carboplatin [102,113,149]. In contrast to MRP and P-gp, the transmembrane transport region of LRP lacks the ATP-binding site specific to ABC transporters.…”