**1. Introduction**

The International Agency for Research on Cancer (IARC) reported that in 2020, an estimated 19.3 million new cancer cases and 10.0 million cancer deaths has occurred. Breast cancer is the most common malignancy in women with nearly 2.3 million new cases (24.2% of all tumor malignancies in women) diagnosed in 2020 [1]. Despite recent advances in treatment, side effects and the development of drug resistance limit the usefulness of current therapies for triple negative breast cancer [2,3].

One of the classical drugs used as chemotherapeutic agent against TNBCs and related cell lines is cisplatin (Figure 1A). Cisplatin has been widely used as antitumor agent in the clinics ever since its discovery in the 1960s. It is estimated that at least half of current therapy protocols employ platinum-based anticancer drugs [4]. Binding of platinum to DNA results in structural deformation of the double-stranded structure, which leads to inhibition of DNA replication and transcription. Subsequently, the DNA damage response leads to apoptosis. The toxicity of cisplatin to normal tissues, like neurotoxicity and hepatotoxicity,

**Citation:** Karami, P.; Othman, G.; Housein, Z.; Salihi, A.; Hosseinpour Feizi, M.A.; Azeez, H.J.; Babaei, E. Nanoformulation of Polyphenol Curcumin Enhances Cisplatin-Induced Apoptosis in Drug-Resistant MDA-MB-231 Breast Cancer Cells. *Molecules* **2022**, *27*, 2917. https:// doi.org/10.3390/molecules27092917

Academic Editor: Nour Eddine Es-Safi

Received: 14 April 2022 Accepted: 26 April 2022 Published: 3 May 2022

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**Copyright:** © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

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along with the acquired therapeutic resistance of cancer cells, reduce the clinical efficacy of this drug [5].

**Figure 1.** The molecular structure of (**A**) Cisplatin (**B**) Curcumin and (**C**) mPEG urethane gemini surfactant nanoparticle.

Curcumin, an extractive of turmeric root, is a natural polyphenol which has been widely reported to possess the anticancer properties (Figure 1B) [6]. The chemical groups of – OH and –OCH3 in curcumin structure, are reported to be responsible for the antioxidant and anti-proliferative properties, respectively [7]. However, the poor bioavailability of curcumin and its instability in physiological media have limited its therapeutic application in clinic [8]. The use of nano carriers in drug delivery systems may increase the solubility, reduce the required dose, attribute to the targeted delivery and, can prolong drug's maintenance in the systemic circulation [9]. Recent works by our lab have shown that the nano-based compounds of curcumin could be employed as an anticancer agents in vitro and in vivo [10,11].

Combination therapies of natural compounds can be employed as a novel strategy in promoting routine drug efficiency and reducing side effects [12]. Curcumin increases the sensitivity of breast cancer cells to cisplatin through down-regulation of FEN1 [13]. It has been demonstrated that curcumin in combination with carboplatin induces apoptosis and suppresses metastasis in human lung and hepatic cancer cells [14,15]. Montopoli et al. suggested that curcumin is an interesting natural polyphenol capable of limiting cell proliferation and possibly, increasing clinical impact of platinum drugs in ovarian cancer patients [16]. More recently, a study confirmed the suppressive effect of curcumin on cisplatin resistance in colorectal cancer cells [17]. These findings support the auxiliary role of curcumin as an adjunct to current chemotherapies and indicate that curcumin could be more effective in combination with chemotherapeutic drugs. This phytochemical in the form of gemini curcumin is more advantageous because of its improved stability, cellular uptake and cytotoxicity (Figure 1C). Gemini surfactants are a class of nano-sized materials consisting of two identical structures liked by a spacer that are highly effective in delivering gene and drugs. Gemini-Cur can trigger apoptosis in cancer cells through modulation of cell cycle and up regulation of apoptotic genes [18].

Here, we investigated the therapeutic effect of the combination of Gemini-Cur and cisplatin as a novel potential therapy on resistance TNBC cells. Gemini-Cur reduces the resistance of MDA-MB-231 to cisplatin through induction of apoptosis.
