3-5-bis(3-4-5-trimethoxybenzylidene)-1-methylpiperidine-4-one and Triple-Negative-Breast-Neoplasms

Triple-negative breast cancer (TNBC) has an aggressive phenotype and a poor prognosis owing to the high propensity for metastatic progression and the absence of specific targeted treatment. Here, we revealed that small-molecule RL71 targeting sarco/endoplasmic reticulum calcium-ATPase 2 (SERCA2) exhibited potent anti-cancer activity on all TNBC cells tested. Apart from apoptosis induction, RL71 triggered excessive autophagic cell death, the main contributor to RL71-induced TNBC cell death. RL71 augmented the release of Ca

Topics: Animals; Apoptosis; Autophagy; Calcium Signaling; Carcinogenesis; Cell Line, Tumor; Curcumin; Diarylheptanoids; Endoplasmic Reticulum Stress; Female; Humans; Intracellular Space; Mice, Nude; Mitochondria; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Signal Transduction; Small Molecule Libraries; Triple Negative Breast Neoplasms; Xenograft Model Antitumor Assays

Patients with triple negative breast cancer have a poor prognosis due in part to the lack of targeted therapies. In the search for novel drugs, our laboratory has developed a second-generation curcumin derivative, 3,5-bis(3,4,5-trimethoxybenzylidene)-1-methylpiperidine-4-one (RL71), that exhibits potent in vitro cytotoxicity. To improve the clinical potential of this drug, we have encapsulated it in styrene maleic acid (SMA) micelles. SMA-RL71 showed improved biodistribution, and drug accumulation in the tumor increased 16-fold compared to control. SMA-RL71 (10 mg/kg, intravenously, two times a week for 2 weeks) also significantly suppressed tumor growth compared to control in a xenograft model of triple negative breast cancer. Free RL71 was unable to alter tumor growth. Tumors from SMA-RL71-treated mice showed a decrease in angiogenesis and an increase in apoptosis. The drug treatment also modulated various cell signaling proteins including the epidermal growth factor receptor, with the mechanisms for tumor suppression consistent with previous work with RL71 in vitro. The nanoformulation was also nontoxic as shown by normal levels of plasma markers for liver and kidney injury following weekly administration of SMA-RL71 (10 mg/kg) for 90 days. Thus, we report clinical potential following encapsulation of a novel curcumin derivative, RL71, in SMA micelles.

Topics: Animals; Apoptosis; Cell Line, Tumor; Cell Proliferation; Curcumin; Diarylheptanoids; Disease Models, Animal; Female; Humans; Maleates; Mice, Inbred BALB C; Mice, SCID; Micelles; Neoplasm Proteins; Styrene; Tissue Distribution; Triple Negative Breast Neoplasms; Xenograft Model Antitumor Assays