Combination of dihydromyricetin and ondansetron strengthens antiproliferative efficiency of adriamycin in K562/ADR through downregulation of SORCIN: A new strategy of inhibiting P‐glycoprotein

Abstract

Though the advancement of chemotherapy drugs alleviates the progress of cancer, long-term therapy with anticancer agents gradually leads to acquired multidrug resistance (MDR), which limits the survival outcomes in patients. It was shown that dihydromyricetin (DMY) could partly reverse MDR by suppressing P-glycoprotein (P-gp) and soluble resistance-related calcium-binding protein (SORCIN) independently. To reverse MDR more effectively, a new strategy was raised, that is, circumventing MDR by the coadministration of DMY and ondansetron (OND), a common antiemetic drug, during cancer chemotherapy. Meanwhile, the interior relation between P-gp and SORCIN was also revealed. The combination of DMY and OND strongly enhanced antiproliferative efficiency of adriamycin (ADR) because of the increasing accumulation of ADR in K562/ADR-resistant cell line. DMY could downregulate the expression of SORCIN and P-gp via the ERK/Akt pathways, whereas OND could not. In addition, it was proved that SORCIN suppressed ERK and Akt to inhibit P-gp by the silence of SORCIN, however, not vice versa. Finally, the combination of DMY, OND, and ADR led to G2/M cell cycle arrest and apoptosis via resuming P53 function and restraining relevant proteins expression. These fundamental findings provided a promising approach for further treatment of MDR.

Roles of Sorcin in Drug Resistance in Cancer: One Protein, Many Mechanisms, for a Novel Potential Anticancer Drug Target

“…Upon doxorubicin treatment, sorcin cellular localization changes, indicating a possible interaction also inside the cell. These findings show that sorcin can limit the toxic effects of doxorubicin (and possibly also of other drugs) in the cell, acting as a drug scavenger [75]. mesenchymal transition (EMT), which generates features associated with high-grade tumors, and leads to metastatic dissemination [67].…”

“…Sorcin transfection in different cancer cell lines, such as leukemia, lung, gastric, ovarian, and breast tumors, leads to increased drug resistance to chemotherapeutic drugs such as doxorubicin, vincristine, paclitaxel, etoposide, homoharringtonine, and 5-fluorouracil [24,25,34,60,66,75,98,99]. Conversely, sorcin silencing reverses MDR in leukemia, HeLa, breast, and colorectal cancer and nasopharyngeal carcinoma [24,26,52,54,60,[66][67][68][69][70].…”

“…Overexpression of many ATP-dependent efflux pumps, and especially ABCB1 (MDR1 or P-glycoprotein), is an important mechanism of resistance to a wide spectrum of chemotherapeutic drugs, including anthracyclines, taxanes, and Vinca alkaloids, in cancer cell lines and in many cancers, e.g., many solid and hematological tumors [100,101]. Sorcin overexpression increases ABCB1 expression, determining increased drug resistance to several drugs, while sorcin silencing decreases expression of ABCB1, increasing cell death, in gastric cancer cells, lung tumor cells, nasopharyngeal carcinoma, cervical carcinoma cells, and leukemias [24,32,34,52,57,60,66,68,69,75]. Sorcin increases ABCB1 expression by stimulating CREB1 phosphorylation by PKA, and binding of activated CREB1 to the cAMP response element (CRE) in the −716-−709 bp of the promoter of the ABCB1 gene [34].…”

“…Part of the MD-resistant phenotype can be attributed to the capacity of sorcin to directly bind chemotherapeutic drugs. In fact, sorcin binds with high-affinity doxorubicin, paclitaxel, vincristine, and cisplatin in vitro, as shown by experiments carried out with techniques such as Surface Plasmon Resonance, fluorescence titration, and X-ray diffraction [75]. Recently, a crystal structure of the sorcin-doxorubicin complex has been solved, allowing the identification of one of the two binding sites for doxorubicin, close to the interface of the two sorcin monomers.…”

“…Recently, a crystal structure of the sorcin-doxorubicin complex has been solved, allowing the identification of one of the two binding sites for doxorubicin, close to the interface of the two sorcin monomers. The doxorubicin molecule is placed between the EF5 loop, the G helix, and the EF4 loop, and is involved in interactions with residues Phe173, Arg174, Asp177, and Tyr188 of the second monomer ( Figure 6) [75]. Upon doxorubicin treatment, sorcin cellular localization changes, indicating a possible interaction also inside the cell.…”