Resveratrol improves the anticancer effects of doxorubicin in vitro and in vivo models: A mechanistic insight
Graphical abstract
Introduction
At present, cancer is the major global health concern with persisted high incidence and mortality rate (Ferlay et al. 2015), despite the availability of wide therapeutic options particularly in chemotherapeutic regimen. Majority of chemotherapeutic drugs have been synthesized based on recognized target genes or proteins associated with cancer cells survival or proliferation pathways (Galustian and Dalgleish 2010). However, most of these drugs are having severe side effects due to cytotoxicity on normal non-target cells. In addition, cancer cells also have capability to confer drug resistance due to increased expression of p-glycoprotein leading to increased efflux of these drugs (Lehne 2000). In the tumor initiation and progression, multiple signaling pathways are diverted to the oncogenic events by altering normal cellular homeostasis (Bianco et al. 2006). Continually studies on cancer depicted a complex network of signaling pathways assisting tumor progression by generating the favorable microenvironment for nourishment of cancer cells (Li et al., 2013, Wang et al., 2012). In the current scenario of chemotherapy, multiple combinations of anticancer drugs are being used for cancer patients, these combinations also evidenced to enhance survival rate. However, success of cancer chemotherapy is still limited due to persistence of several others reasons like drug resistance, target of non-cancer cells, metabolic stresses, which lead to severe side effects (Iwamoto 2013). Therefore, a novel combination of chemotherapeutic drugs is primarily required to solve all these issues (Kummar et al., 2010, Wang et al., 2010). From the last several years, combinations of chemotherapeutic drugs with phytochemicals have become a major area of research for all the oncologists. It is because; phytochemicals have reported to enhance chemo-sensitivity or therapeutic efficacy and limits high toxicity of chemotherapeutic drugs (Bolhassani 2015).
Doxorubicin (DOX) is widely used anticancer drug against different human malignancies; it has severe side effects in the form of typhlitis, cardiotoxicity, nephrotoxicity, hepatotoxicity and other toxicity (Pestalozzi et al., 1993, Rashid et al., 2013, Singal and Iliskovic, 1998). Doxorubicin causes a high cellular level of ROS to kill cancer cells; however, necrotic cell death is most predominant in killing of cancer cells, which generated inflammatory micro-environment, which also become a reason for undesired cellular toxicity (Thakur et al. 2008). Hence, doxorubicin alone is not preferable drug. A range of phytochemicals available showed a chemo-preventive effect and sensitize cancer cells toward doxorubicin (Vinod et al. 2013). Among diverse group of phytochemicals, resveratrol (RSVL) has proven their strong chemo-preventive effects in various types of human tumors (Delmas et al., 2014, Kim et al., 2014, Siddiqui et al., 2015), and shown to prevent initiation, promotion and progression of cancer (George et al., 2011, Roy et al., 2009). RSLV is a well known antioxidant and phenolic compound, and promoted growth-arresting ability of anticancer drugs with minimizing cellular toxicity generated by chemotherapeutic drugs (Delmas et al., 2011, Kim et al., 2014). These research outcomes suggested that RSVL governs redox homeostasis, inflammation, cell proliferation and death by modulating cancer associated signaling pathways (Colin et al., 2014, Tosetti et al., 2009). However, the mode of action of RSVL in combination with DOX has not been well understood in depth. Motivated by the present understanding of combination effect of drugs and phytochemicals, we made an effort to delineate the molecular pathways modulated by combined effect of DOX and RSV in breast cancer cell lines and Ehrlich ascitic carcinoma (EAC) mice model.
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Cell culture and cytotoxicity assays
Human breast cancer cell lines, MCF-7 and MDA-MB-231 were obtained from National Centre for Cell Science (NCCS), Pune. Cells were grown in RPMI-1640 and supplemented with 10% fetal bovine serum (FBS), penicillin (100 units/ml), streptomycin (100 µg/ml) and culture was maintained. The cell viability assay was performed following Carmichael et al. (Carmichael et al. 1987) in both type of cells in range of doses of RSVL and DOX for 24 h and 48 h (Fig. 1). Selected doses of RSVL and DOX below its IC50
Evaluation of cell viability and morphological changes in breast cancer cell lines after combination treatment of RSVL and DOX
The cytotoxicity activity of both DOX and RSVL were tested alone at a range of doses in MCF-7 and MDA-MB-231 breast cancer cell lines. It was observed that MCF-7 was more sensitive to administered drugs than MDA-MB-231 cells, as depicted from their *IC50 values (Fig. 1A–D, Table 1). Further, the synergistic effects of combinatorial treatment of DOX and RSVL were evaluated from their cumulative index (CI). It was observed that IC20 dose of DOX and IC30 dose of RSVL in combination (R30D20) had
Discussion
Chemotherapy is one of the most common therapeutic regimens for cancer; however, in majority of cases it causes severe side effects. Thus, novel therapeutic strategies are required, which have lesser side effects with enhanced anticancer activity. The use of phytochemicals with therapeutic drug is one of the novel strategies to achieve this goal. RSLV, a well-known polyphenolic compound have investigated its potential as chemo sensitizer for doxorubicin both in-vitro and in-vivo systems (Kim et
Conflict of interest
None
Acknowledgment
Authors are thankful to Council of Scientific & Industrial Research, New Delhi for funding this work from network project BSC0111, and we are also thankful to UGC for providing senior research fellowship to Mr. Girish Rai. Mr. Puneet Khare is highly acknowledged for flow cytometery and Mr. S. H. N Naqvi is also acknowledged for helping in animal study.
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2021, Phytomedicine PlusCitation Excerpt :RSV reduces colony formation rate in MDA-MB-435 and MDA-MB-231 cancer cells in a similar fashion to genistein (Khongsti et al., 2021a). In agreement with this, RSV treatment inhibits cell proliferation, colony formation, invasion, and induces apoptosis in MCF-7 (Rai et al., 2016), MDA-MB-231 breast cancer cells (Sprouse and Herbert, 2014), and in colorectal cancer cells (Buhrmann et al., 2016). Further, RSV in combination with doxorubicin is shown to reduce cell growth, migration, and also influence apoptosis in adriamycin-resistant MCF7 breast cancer cells (Jin et al., 2019).