Amelioration of Doxorubicin-Induced Cardiotoxicity by an Anticancer-Antioxidant Dual-Function Compound, HO-3867

Abstract

Doxorubicin (DOX) is a drug commonly used for the treatment of cancer. The development of resistance to DOX is common, and high cumulative doses cause potentially lethal cardiac side effects. HO-3867 (3,5-bis(4-fluorobenzylidene)-1-[(2,2,5,5-tetramethyl-2,5-dihydro-1-hydroxy-pyrrol-3-yl)methyl]piperidin-4-one), a synthetic curcumin analog, has been shown to exhibit both anticancer and cardioprotective effects. However, its cardioprotection in the setting of a conventional cancer therapy has not been established. This work investigated the use of HO-3867 and DOX to achieve a complementary outcome, i.e., increased toxicity toward cancer cells, and reduced cardiac toxicity. Combination treatment was investigated using DOXresistant MCF-7 breast cancer cells [MCF-7 multidrug-resistant (MDR)] and BALB/c mice. Lower doses of HO-3867 and DOX (5 and 2.5 M, respectively) reduced viability of MCF-7 MDR cells to an extent significantly greater than that when either drug was used alone, an effect equivalent to that induced by exposure to 50 M DOX. In normal cardiac cells, the loss of viability from combination treatment was significantly lower than that induced by 50 M DOX. Increases in apoptotic markers, e.g., cleaved caspase-3, and decreases in fatty acid synthase and pAkt expressions were observed by Western blotting. Mice treated with both HO-3867 and DOX showed significant improvement in cardiac functional parameters compared with mice treated with DOX alone. Reduced expression of Bcl-2 and pAkt was observed in mice treated with DOX alone, whereas mice given combination treatment showed levels similar to control. The study indicates that combination treatment of HO-3867 and DOX is a viable option for treatment of cancer with reduced cardiotoxic side effects.

HO-3867, a curcumin analog, sensitizes cisplatin-resistant ovarian carcinoma, leading to therapeutic synergy through STAT3 inhibition

“…The compounds have previously been reported to inhibit the proliferation of a variety of cancer cells in vitro, and ovarian cancer xenograft tumors in vivo. [19][20][21]31 In the present report, we have demonstrated that the DAP compounds, used in combination with cDDP, exhibit a significant induction of cell cycle arrest and apoptosis in cDDP-resistant human ovarian cancer with therapeutic synergy apparently due to resensitization to cisplatin toxicity through downregulation of STAT3-signaling pathway.…”

The Pleiotropic Effects of Curcumin.

“…It was seen that that the cytotoxic activity of the combination was better than either doxorubicin or HO-3867 on its own. But the cytotoxicity of doxorubicin on the normal cells ( used as control ) was diminished by the addition of HO-3867 to doxorubicin [45] .…”

“…An in vitro study done on MCF-7 breast cancer cells some of which were partially doxorubicin resistant, HO-3867 ( which is a synthetic curcumin compound), was used in combination with doxorubicin to see the anti cancer effect of the combination as well as to see the cardioprotective action of HO-3867 on normal cardiac cells and endothelial cells of the aorta which were used as controls [45] . It was seen that that the cytotoxic activity of the combination was better than either doxorubicin or HO-3867 on its own.…”

Development of pituitary tumor-transforming gene (PTTG) transgenic mice for the treatment of ovarian cancer.

“…MDR-l down regulation was achieve through inactivation of signaling pathways Akt, ERK, p38, JNK, and NF-KB in a COX-2 dependent manner. A synthetic analog of curcumin HO-3867 has also been used in the same manner to achieve a complementary outcome with Dox to increase cancer cell toxicity without cardiotoxicity [164]. Using this combination therapy, they were able to decrease the concentration of Dox from 50llM to 2.51lM to achieve the same anti-proliferative effect in Dox-resistant breast cancer cell line MCF-7 MDR and showed decreased expression of Bcl-2 and pAkt.…”

“…Combining Dox with sildenafil resulted in enhanced cell death through the down regulation of Bcl-2 coupled to an increase in caspase 3 and enhanced the Dox-induced generation of reactive oxygen species (ROS) while attenuating Dox-induced cardiac dysfunction [163]. Dox has also been combined with HO-3867, a synthetic curcumin analog, to achieve enhanced cell death and reduced cardiotoxicity through the use of lower doses of Dox [164]. Interestingly chebulagic acid, a COX- Raf/MEKIERK signaling be intact for its mechanism of action to occur [167,168], therefore the ERK inhibitor sorafenib acts counter to Dox, resulting in increased cell survival and reduced formation of autophagic vesicles [166].…”